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Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

Ilaria Proietti, Nevena Skroza, Nicoletta Bernardini and 11 more

Cancers · 2020 · Review · CC BY

Abstract

Simple Summary. Patients with advanced melanoma are often treated with v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors. Although these agents prolong life, patients inevitably develop resistance and their cancer progresses. This review examines all of the potential ways that melanoma cells develop resistance to BRAF inhibitors. These mechanisms involve genetic and epigenetic changes that activate different signaling pathways, thereby bypassing the effect of BRAF inhibition, but they also involve a change in cell phenotype and the suppression of anticancer immune responses. Currently, BRAF inhibitor resistance can be partially overcome by combining a BRAF inhibitor with a mitogen-activated protein kinase kinase (MEK) inhibitor, but many other combinations are being tested. Eventually, it may be possible to choose the best combination of drugs based on the genetic profile of an individual’s cancer.

Abstract. This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 27, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1Although melanoma is the least common type of skin cancer, it is the most deadly, causing approximately 61,000 deaths per year around the world. An estimated 42–45% of melanomas harbor mutations of the gene for v-Raf murine sarcoma viral oncogene homolog B (BRAF), an activating serine/threonine protein kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. In patients with cutaneous melanoma, almost all of these mutations affect codon 600 of exon 15. The most common mutations are V600E (accounting for ~80% of BRAF mutations), in which a single nucleotide substitution (GTG to GAG) results in valine being substituted for glutamate, and V600K (accounting for ~16% of BRAF mutations), where two nucleotides are affected (GTG to AAG), resulting in valine being substituted for lysine. Other BRAF mutations include V600D and V600R (together accounting for ~3%).

2These mutations are oncogenic drivers that cause tumor progression and metastasis, and their discovery led to the development of small molecule inhibitors of BRAF, including vemurafenib, dabrafenib and encorafenib, for the treatment of melanoma. Testing for BRAF mutations is now globally recommended in order to choose the most appropriate therapy for patients with stage III or IV melanoma.

3BRAF inhibitors dramatically improved response rate and survival compared with standard chemotherapy in patients with BRAF-mutated melanoma, but these benefits were not durable, and most patients developed progressive disease as a result of resistance development. Consequently, the recommended treatment approach for patients with advanced or metastatic BRAF-mutated melanoma is now a combination of a BRAF inhibitor and a MAPK kinase (MEK) inhibitor.

4Only through thorough understanding of the mechanisms of BRAF inhibitor resistance can we hope to develop strategies for achieving the full therapeutic potential of contemporary treatments in patients with melanoma. Therefore, the aim of the current systematic review was to thoroughly investigate the literature on acquired BRAF inhibitor resistance, in order to identify future potential treatment strategies. Based on what is known about mechanisms of BRAF inhibitor resistance, four predefined topics were examined: (1) the genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms of resistance; (3) influence of the immune system on BRAF inhibitor resistance; and (4) the potential of combination therapy to overcome resistance.

2. Methods

5We undertook a search of the MEDLINE database on May 18, 2020 for any articles on BRAF inhibitor resistance, when used alone or in combination with a MEK inhibitor, in patients with cutaneous melanoma (a full description of the searches is shown in Supplementary Materials) published since the beginning of 2010. Four separate searches were undertaken on each predefined topic. We excluded conference reports/abstracts, news items and case reports, and articles published in languages other than English.

6One author (IP) reviewed the search results and chose potential articles based on the title and abstracts. Articles were rejected from the review if they were not specific to acquired BRAF resistance (i.e., the focus was on primary resistance) in cutaneous melanoma (i.e., excluding ocular or mucosal melanoma).

7From this group of articles, those most likely to contain pertinent information about BRAF inhibitor resistance mechanisms were extracted for discussion.

3. Results

8The search identified the following number of articles: (1) 406 on genetic mechanisms, (2) 46 on epigenetic mechanisms; (3) 82 on immune mechanisms; and (4) 499 on overcoming resistance with combination therapy.

9A more in-depth review of the articles meant that additional articles were excluded as being either not relevant or not an included article type, and some articles were reclassified into another topic section. The final number of articles included in each section were: (1) 106 articles on genetic mechanisms; (2) 61 articles on epigenetic or transcriptomic mechanisms; (3) 23 articles on immune mechanisms; and (4) 189 articles on overcoming resistance. There was some overlap between sections as some articles were relevant to more than one topic.

3.1. Genetic Mechanisms of Resistance

10Advances in genetic analytical techniques, such as next generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR) have considerably expanded our knowledge of the genetic changes involved in BRAF inhibitor resistance, and raise the possibility of incorporating mutational information into predictive or prognostic models.

11A range of genetic mutations have been identified as causing acquired BRAF resistance (recently reviewed by Tian and Guo and summarized in Table 1). The most common mutations are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and MEK1/2 mutations, and these appear to be associated with different disease phenotypes. For example, brain metastases appear to be associated with NRAS mutations whereas hepatic progression is associated with MEK1/2 mutations. Longitudinal assessments indicate that patients tend to accumulate resistance-related mutational changes over time. However, the rate of resistance development does not appear to be related to the antitumor activity of the BRAF inhibitor (i.e., the speed at which the BRAF inhibitor kills treatment-sensitive cells has no bearing on the speed at which resistant clones develop).

12Splice variants of BRAF mediate resistance by affecting BRAF dimerization. In cells with wild-type BRAF, activation by RAS leads to the formation of homodimers (BRAF-BRAF) or heterodimers with CRAF (BRAF-CRAF), whereas cells with V600E mutations do not form dimers and activate MEK via monomeric BRAF. BRAF inhibitors are ineffective in melanoma with wild-type BRAF because the homo- and heterodimers retain their signaling capacity, whereas these inhibitors block the action of monomeric BRAF. Splice variants of BRAF V600E are also able to form dimers and therefore to activate MEK in the presence of BRAF inhibitors.

13Genetic changes to key molecules in the NRAS/BRAF/MEK pathway lead to reactivation of the previously blocked MAPK pathways or activation of alternative signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway (Figure 1). In some patients with BRAF inhibitor resistance, the activation of PI3K/AKT is driven by loss of phosphatase and tensin homolog (PTEN) expression.

14The genetic changes also contribute to the increased cytoprotective autophagy seen in BRAF inhibitor-resistant melanoma cells, allowing tumor cell proliferation to continue unchecked. The enhanced autophagic-lysosomal activity of BRAF-resistant melanoma cells exacerbates adenosine triphosphate (ATP) secretion, which in turn increases melanoma cell invasion.

15However, some mutations are independent of downstream pathways. Overexpressed genes in BRAF inhibitor-resistant cells are often associated with growth factors and their receptors, cell adhesion molecules and extracellular matrix binding. Common mutations involve effects on receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor (HGF), or insulin-like growth factor (IGF) receptor, which in turn activate parallel pathways. Research has shown extensive redundancy in RTK-mediated signaling pathways, whereby a broad range of widely expressed RTKs are upregulated in cells with BRAF inhibitor resistance. These changes are mediated post-translationally via the inhibition of proteolytic ‘shedding’ of cell surface receptors. This shedding is a normal part of the negative feedback loop that limits intracellular signaling, but is blocked by BRAF inhibitors. As a result, there is an increase in cell surface receptor levels in the tumor during treatment, causing activation or enhancement of alternative signaling pathways.

16Transcriptomic analysis showed that, compared with BRAF inhibitor-sensitive cells, those with acquired resistance had differences in 887 upregulated genes and 1014 downregulated genes. Upregulated genes were mainly Group IV genes involved in inflammatory response, cell migration, exocrine system development, regulation of peptidase activity and tissue development, or Group V genes involved in cellular response to lipopolysaccharide, regulation of epithelial cell apoptosis, processes involved in the ovulation cycle, and regulation of interleukin (IL)-1β production (Figure 2).

17The contribution to resistance of genetic alterations in cell cycle regulators is an interesting finding. One such change is upregulation of the cell cycle genes CDK6 and CCND1. This appears to open up the possibility of using CDK inhibitors to overcome resistance; preclinical data indicate that adding palbociclib to treatment with BRAF inhibitors and/or MEK inhibitors prevented resistance development in treatment-naïve melanoma cells and animal models, but did not overcome resistance in cells and animals with acquired BRAF inhibitor resistance.

18Other genetic changes implicated in the development of vemurafenib resistance are loss of genes that encode NF1 (a negative regulator of RAS) and CUL3 (a key protein in the ubiquitin ligase complex). Loss of CUL3 is associated with increased RAC1 activity. RAC1 is a member of Rho family of GTPases that regulate actin dynamics, cytoskeleton organization, and cell motility. Rho GTPases regulate gene transcription via the downstream co-activator YAP1. Inhibition of actin remodeling, possibly by inhibiting YAP1, has been suggested as a potential target for overcoming BRAF inhibitor resistance. Actin is not the only cytoskeleton protein implicated in BRAF inhibitor resistance: differentially regulated genes coding for microtubules and the intermediate filament nestin are also involved.

19The net effect of these genetic alterations is a shift in the phenotype of BRAF inhibitor-resistant melanoma cells, resulting in an epithelial-to-mesenchymal transition (EMT), characterized by changes in cell–cell adhesion, cell-matrix adhesion, cellular polarity, and the cytoskeleton. As well as being mediated by the genetic changes within the cell, this EMT shift is also stimulated by nearby fibroblasts in the tumoral stroma, which secrete growth factors (such as HGF) that strongly activate the MAPK cascade.

3.2. Epigenetic and Transcriptomic Mechanisms

20Plasticity of the melanoma cell phenotype is often driven by changes in the tumor microenvironment, such as hypoxia, pH, and nutrient supply. BRAF inhibitor treatment is also associated with a change in the metabolic profile of cells, with a shift towards more mitochondrial respiration and the formation of reactive oxygen species.

21These changes in the cellular metabolic profile and in the tumor microenvironment affect the activity of histone-modifying enzymes, including histone methyltransferase, histone demethylase, and histone deacetylase (HDAC). These changes modulate transcription by modifying chromatin structure. For example, the increased oxidative metabolism in BRAF inhibitor-treated cells causes a shift from glucose to glutamine metabolism, with increased glutamine catabolism. Low glutamine levels in the core of a melanoma induce histone hypermethylation and BRAF inhibitor resistance. BRAF inhibitor-resistant cells show increased expression of KDM5B, a histone demethylase enzyme.

22Downregulation of a range of HDAC genes have been reported to be associated with BRAF inhibitor resistance, including SIRT2 (encoding for sirtuin 2), SIRT6 (encoding for sirtuin 6), and HAT1 (encoding for histone acetyltransferase 1). On the other hand, HDAC8 is upregulated in BRAF inhibitor-resistant cells.

23Noncoding portions of DNA are also implicated in the development of resistance, particularly loci that are involved in transcription factor recruitment and occupancy. Long non-coding RNA (lncRNA) loci are also implicated; transcriptional activation of one such lncRNA, EMICERI, activates a neighboring gene that confers resistance to BRAF inhibitors.

24BRAF inhibitor resistance involves a range of transcription factors (Table 2). A transcriptomic analysis of BRAF inhibitor-resistant melanoma cells showed that some transcription factors were upregulated whereas others were downregulated. These researchers highlighted a set of transcriptional ‘master regulators’ including STAT, FOXO, ZEB1 (upregulated) and MITF, HIF1A and MYB (downregulated) that control a range of effector pathways (Figure 3). One of the key processes regulated by these transcription factors is ErbB3 phosphorylation, which leads to PI3K/AKT activation. Downstream effects of these transcription-related events include inhibition of apoptosis and the EMT phenotypic change seen in BRAF inhibitor-resistant cells.

25Resistance is also mediated at a post-transcriptional level through effects on translation mediated by RNA binding proteins (e.g., human antigen R and 4E-BP), translation initiation complexes (e.g., eIF4F or eIF4E), micro-RNAs (Table 2), and by modifications in wobble tRNA. Some of these micro-RNAs (e.g., miR-199b-5p) are regulators of cell-cell signaling via VEGF and HIF-1α, while others (e.g., miR-4488 and miR-4443) are involved in autophagy regulation.

3.3. Immune Mechanisms

26The genetic and epigenetic changes associated with BRAF inhibitor treatment affect the interaction between the melanoma tumor and the immune system in various ways. Untreated melanoma is not particularly immunogenic, but treatment with BRAF inhibitors causes a transient increase in antitumor immunogenicity, with recruitment of T-cells and natural killer (NK) cells and a reduction in regulatory T-cells (Tregs).

27Treated patients may develop immune-related adverse events (e.g., arthralgia, immune-related skin reactions), which can be a marker of response to BRAF inhibitors. However, once resistance to BRAF inhibitors develops, the tumor microenvironment reverts to its low immunogenic state, with fewer infiltrating T-cells and NK cells, more double-negative T-cells, and restoration of myeloid-derived suppressor cells. Moreover, the T-cells and NK cells that are present are functionally impaired compared with BRAF inhibitor-sensitive tumors, such that cytotoxic T-lymphocytes and NK cells are less effective at recognizing and killing BRAF inhibitor-resistant cells.

28In the tumor cell, this reversion to a low immunogenic state is caused by induced expression of programmed cell death ligand-1 (PD-L1), increased expression of the immunoregulatory protein Galactin-1, and increased expression of CD47, an immunoregulatory cell marker, on tumor cells, leading to reduced killing by cytotoxic T-cells and macrophages. BRAF inhibitor-resistant tumor cells also show reduced expression of target antigens, and increased production of IL-10. They also show upregulation of the IGF receptor, which sensitizes BRAF inhibitor-resistant cells to the effects of cytotoxic T-lymphocytes by increasing the cellular uptake of granzyme B.

29Another change which may have therapeutic implications is the restoration of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) expression. CEACAM1 is an intercellular adhesion molecule that regulates cell proliferation, cellular energetics, and inflammation in cancer cells, including melanoma, and has a role in regulating the immune cells in the tumor microenvironment. CEACAM1 is downregulated prior to resistance development, suggesting that it may be a future target for the treatment of BRAF inhibitor-resistant melanoma.

30In addition to the changes within the tumor cell, secreted soluble factors originating from macrophages in the tumor microenvironment contribute to resistance, including tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF), which contribute to tumor cell growth and invasion, and further infiltration of macrophages and T-lymphocytes into the tumor microenvironment.

3.4. Overcoming Resistance via Treatment Combinations

31The standard of care for BRAF-mutated melanoma is now the combination of BRAF inhibitors and MEK inhibitors, as there is considerable high-quality evidence from randomized comparative studies that this approach prolongs progression-free survival (PFS) and overall survival (OS) compared with BRAF inhibitor monotherapy. Some patients are able to achieve a durable response lasting ≥ 5 years with such combinations.

32MEK inhibitors block the MEK/ERK signaling pathway that is activated in cells during treatment with BRAF inhibitors, thereby delaying the development of resistance and increasing the duration of response. MEK inhibitors also suppress the production of PD-L1, and so help to suppress immune activation that occurs during BRAF inhibition. The most extensively researched BRAF inhibitor + MEK inhibitor combinations are vemurafenib + cobimetinib, dabrafenib + trametinib, and encorafenib + binimetinib.

33While there are no head-to-head comparisons of these combinations, some differences do exist. Encorafenib has the highest paradox index of the three BRAF inhibitors. This index is a ratio of the EC80 for ERK activation relative to the IC80 of BRAF inhibitor-resistant cell growth, and provides a measure of the therapeutic window for antitumor activity before paradoxical ERK activation. The paradox index of encorafenib is 50, compared with 10 for dabrafenib and 5.5 for vemurafenib. This difference may help to explain the higher efficacy of encorafenib monotherapy compared with vemurafenib monotherapy in the COLUMBUS study.

34Although these combinations have not been directly compared, the combination of encorafenib + binimetinib was associated with numerically longer OS and PFS in the COLUMBUS study than was seen with vemurafenib + cobimetinib in the coBRIM study or dabrafenib + trametinib in the COMBI-v study. While the overall rate of adverse events with each combination was similar, encorafenib + binimetinib was associated with a lower incidence of pyrexia compared with dabrafenib + trametinib and of photosensitivity compared with vemurafenib + cobimetinib.

35Once patients progress after BRAF inhibitor + MEK inhibitor treatment, the recommended second-line approach is immunotherapy with an immune checkpoint inhibitor. Some patients who progress on BRAF inhibitor treatment may benefit from a rechallenge with BRAF inhibitor + MEK inhibitor therapy.

36Preliminary (phase Ib and II) clinical trials have been conducted using triple therapy with a BRAF inhibitor + MEK inhibitor + PD-L1 inhibitor in mostly BRAF inhibitor-naïve patients, with high rates of response (63–73%). In the comparative phase II study, triplet therapy prolonged PFS compared with the BRAF inhibitor + MEK inhibitor doublet combination (median 16.0 vs. 10.3 months; p = 0.043), but was associated with more than two times the rate of grade 3 or 4 adverse events (58.3% vs. 26.7%).

37The diversity of genetic changes driving resistance, and the inter- and intra-individual heterogeneity of resistance-associated mutations complicates treatment of BRAF inhibitor-resistant melanoma. One potential approach is to silence the expression of specific genes using small interfering RNA (siRNA). However, the clinical application of this approach is hampered by difficulties in delivering siRNA into the cytoplasm of tumor cells without the use of viral vectors, which can cause mutation, immune activation, or inflammation. To the best of our knowledge, none of the non-viral vectors for siRNA have reached clinical investigation in melanoma.

38In addition to heterogeneous genetic changes, there are a range of phenotypic adaptations to BRAF inhibition, indicating that several alternative signaling routes are involved in overcoming BRAF resistance. Because BRAF inhibitor-resistant cells have developed a range of ‘escape routes’, it is likely that multiple different treatment targets will be required to overcome resistance. Therefore, researchers have investigated targeting node points in the activated pathways. Based on the activation/overexpression of transmembrane receptors or RTKs and activation of alternative signaling pathways, some of the novel combinations being tested in vitro include BRAF inhibitors with: TGF-β receptor inhibitors, inhibitors of growth factor receptors or RTKs (e.g., gefitinib, sorafenib, dovinitib), PI3K/mTOR inhibitors, bifunctional MAPK/PI3K antagonists, anaplastic lymphoma kinase (ALK) inhibitors, novel MEK and/or aurora kinase inhibitors, MAPK activators, glucocorticoid receptor antagonists, CDK4/6 inhibitors, ERK1/2 inhibitors, CRAF inhibitors, pan-RAF inhibitors, heat shock protein (HSP) inhibitors, or MCL1 inhibitors. However, few of these combinations have been investigated clinically.

39One of the few combinations to be investigated in clinical trials is the combination of a BRAF inhibitor (vemurafenib) with an HSP90 inhibitor (XL888). This combination was tested in an open-label phase I study in 21 patients with BRAF V600E-mutated metastatic melanoma, but none of the patients had received BRAF inhibitors before, so none had acquired resistance. The objective response rate in the 20 evaluable patients was 75%, with three complete responses and 12 partial responses, and the 1-year OS rate was 60%. The most common grade 3 adverse events were skin toxicities (rash, squamous cell carcinoma, and new primary melanoma), diarrhea, headache, and fatigue. The authors reported that they will be undertaking another clinical trial with the triplet combination of vemurafenib, cobimetinib, and XL888, but note that reduced doses of the BRAF and MEK inhibitors may be needed to limit toxicity with this combination.

40Epigenetic mechanisms may be targeted by inhibiting key transcription factors, such as WNT5 or STAT3, or by the use of microRNA mimetics or HDAC inhibitors. HDAC inhibitors have also been investigated in combination with a CDK inhibitor with promising in vitro and in vivo activity. A single-arm, open-label, proof-of-concept study is underway in the Netherlands to investigate the effect of the HDAC inhibitor vorinostat in patients with BRAF V600E-mutated resistant melanoma (NCT02836548). Patients who progress on treatment with a BRAF inhibitor and/or a combination of a BRAF inhibitor + MEK inhibitor will receive 14 days of treatment with vorinostat, before reinitiating their earlier BRAF/MEK inhibitor treatment. The aim of the study is to see whether vorinostat can purge the resistant clones and re-establish responsiveness to BRAF/MEK inhibitor treatment.

41Agents targeting the immune system are also being investigated for the treatment of BRAF inhibitor resistance. As described earlier, the use of immune checkpoint inhibitors in combination with a BRAF inhibitor + MEK inhibitor appears to be effective but is associated with a high rate of toxicity. Other potential immune-targeted therapies undergoing preclinical investigation include adoptive T-cell therapy, dendritic cell vaccination, and combining BRAF inhibitor treatment with a toll-like receptor 7 agonist (e.g., imiquimod).

42A considerable number of preclinical studies are investigating other novel targets for overcoming BRAF inhibitor resistance. These include combining BRAF and/or MEK inhibitors with inhibitors of pre-mRNA splicing (to counteract resistance caused by BRAF splicing), BH3-mimetics, BCL2 inhibitors, mitochondrial-targeted agents, inhibitors of p90 ribosomal S6 kinases, pro-caspase activating compounds, Rho kinase 1 (ROCK1) inhibitors, protein kinase Cδ inhibitors, tubulin inhibitors, ErbB2 or ErbB3 inhibitors, activators of the liver-X nuclear hormone receptor, an antibody conjugate targeting the endothelin B receptor, monoclonal antibodies against chondroitin sulfate proteoglycan 4, inhibitors of sterol regulator element binding protein I (SREBP-1), copper chelators, polo-like 3 kinase inhibitors (including in models of BRAF + MEK inhibitor resistance), anti-nodal antibodies, PAK1 inhibitors, GLI1/2 inhibitors, inhibitors of IQ motif-containing GTPase activating protein 1 (IQGAP1), serotonin agonists, CK2 inhibitors, p53 activators, metformin, statins, non-steroidal anti-inflammatory drugs, mibefradil, hydroxychloroquine (an autophagy inhibitor), and A100 (a reactive oxygen species-activated prodrug).

4. Future Directions

43As described above, considerable research is being undertaken to identify potential new combinations of treatments that may limit or prevent the development of BRAF inhibitor resistance, or overcome resistance once developed. In addition to this, investigations are underway to improve existing therapies, such as employing nanovehicle technology to enhance the safety or targeted delivery of drugs, which may enable the use of higher doses or more potent combinations of existing agents. Preclinical studies have investigated the encapsulation of MEK inhibitors in pegylated nanoliposomes for oral administration, or the topical administration of BRAF inhibitor-loaded nanovehicles into melanoma lesions using a microneedling technique.

44The multiplicity of potential targets raises the possibility of using genomic and proteomic data to personalize combination therapy towards the specific pathway that is activated during BRAF inhibitor resistance in individual patients with melanoma. Investigators are developing an MAPK pathway activity score from aggregated gene expression data that could help to determine the best drug combination to use, but further validation is needed.

5. Conclusions

45Given the complexity and heterogeneity of pathways involved in BRAF inhibitor resistance, a ‘one size fits all’ approach to overcoming acquired resistance is unlikely to succeed. However, the plethora of research in this field means that multiple promising leads are being identified and investigated, which bodes well for the development of new treatment approaches for patients with acquired BRAF inhibitor resistance.

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Feddersen C.R., Schillo J.L., Varzavand A., Vaughn H.R., Wadsworth L.S., Voigt A.P., Zhu E.Y., Jennings B.M., Mullen S.A., Bobera J., et al. Src-Dependent DBL Family Members Drive Resistance to Vemurafenib in Human Melanoma. Cancer Res. 2019;79:5074-5087.
Not in our library10.1158/0008-5472.can-19-0244
27.
Gibney G.T., Smalley K.S. An unholy alliance: Cooperation between BRAF and NF1 in melanoma development and BRAF inhibitor resistance. Cancer Discov. 2013;3:260-263.
Not in our library10.1158/2159-8290.cd-13-0017
28.
Girotti M.R., Pedersen M., Sanchez-Laorden B., Viros A., Turajlic S., Niculescu-Duvaz D., Zambon A., Sinclair J., Hayes A., Gore M., et al. Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov. 2013;3:158-167.
Not in our library10.1158/2159-8290.cd-12-0386
29.
Gross A., Niemetz-Rahn A., Nonnenmacher A., Tucholski J., Keilholz U., Fusi A. Expression and activity of EGFR in human cutaneous melanoma cell lines and influence of vemurafenib on the EGFR pathway. Target. Oncol. 2015;10:77-84.
Not in our library10.1007/s11523-014-0318-9
30.
Gupta R., Bugide S., Wang B., Green M.R., Johnson D.B., Wajapeyee N. Loss of BOP1 confers resistance to BRAF kinase inhibitors in melanoma by activating MAP kinase pathway. Proc. Natl. Acad. Sci. USA. 2019;116:4583-4591.
Not in our library10.1073/pnas.1821889116
31.
Hintzsche J., Kim J., Yadav V., Amato C., Robinson S.E., Seelenfreund E., Shellman Y., Wisell J., Applegate A., McCarter M., et al. IMPACT: A whole-exome sequencing analysis pipeline for integrating molecular profiles with actionable therapeutics in clinical samples. J. Am. Med. Inform. Assoc. 2016;23:721-730.
Not in our library10.1093/jamia/ocw022
32.
Hu W., Jin L., Jiang C.C., Long G.V., Scolyer R.A., Wu Q., Zhang X.D., Mei Y., Wu M. AEBP1 upregulation confers acquired resistance to BRAF (V600E) inhibition in melanoma. Cell Death Dis. 2013;4:e914.
Not in our library10.1038/cddis.2013.441
33.
Inozume T., Tsunoda T., Morisaki T., Harada K., Shirasawa S., Kawamura T. Acquisition of resistance to vemurafenib leads to interleukin-10 production through an aberrant activation of Akt in a melanoma cell line. J. Dermatol. 2018;45:1434-1439.
Not in our library10.1111/1346-8138.14651
34.
Jain A., Tripathi R., Turpin C.P., Wang C., Plattner R. Abl kinase regulation by BRAF/ERK and cooperation with Akt in melanoma. Oncogene. 2017;36:4585-4596.
Not in our library10.1038/onc.2017.76
35.
Janostiak R., Malvi P., Wajapeyee N. Anaplastic Lymphoma Kinase Confers Resistance to BRAF Kinase Inhibitors in Melanoma. iScience. 2019;16:453-467.
Not in our library10.1016/j.isci.2019.06.001
36.
Johannessen C.M., Boehm J.S., Kim S.Y., Thomas S.R., Wardwell L., Johnson L.A., Emery C.M., Stransky N., Cogdill A.P., Barretina J., et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968-972.
Not in our library10.1038/nature09627
37.
Downregulation of the Ubiquitin Ligase RNF125 Underlies Resistance of Melanoma Cells to BRAF Inhibitors via JAK1 Deregulation · 2015
Not checked
38.
Konermann S., Brigham M.D., Trevino A.E., Joung J., Abudayyeh O.O., Barcena C., Hsu P.D., Habib N., Gootenberg J.S., Nishimasu H., et al. Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature. 2015;517:583-588.
Not in our library10.1038/nature14136
39.
Krayem M., Aftimos P., Najem A., van den Hooven T., van den Berg A., Hovestad-Bijl L., de Wijn R., Hilhorst R., Ruijtenbeek R., Sabbah M., et al. Kinome Profiling to Predict Sensitivity to MAPK Inhibition in Melanoma and to Provide New Insights into Intrinsic and Acquired Mechanism of Resistance Short Title: Sensitivity Prediction to MAPK Inhibitors in Melanoma. Cancers. 2020;12:512.
Not in our library10.3390/cancers12020512
40.
Lehraiki A., Cerezo M., Rouaud F., Abbe P., Allegra M., Kluza J., Marchetti P., Imbert V., Cheli Y., Bertolotto C., et al. Increased CD271 expression by the NF-kB pathway promotes melanoma cell survival and drives acquired resistance to BRAF inhibitor vemurafenib. Cell Discov. 2015;1:15030.
Not in our library10.1038/celldisc.2015.30
41.
Lei F.X., Jin L., Liu X.Y., Lai F., Yan X.G., Farrelly M., Guo S.T., Zhao X.H., Zhang X.D. RIP1 protects melanoma cells from apoptosis induced by BRAF/MEK inhibitors. Cell Death Dis. 2018;9:679.
Not in our library10.1038/s41419-018-0714-7
42.
Lin L., Bivona T.G. The Hippo effector YAP regulates the response of cancer cells to MAPK pathway inhibitors. Mol. Cell. Oncol. 2016;3:e1021441.
Not in our library10.1080/23723556.2015.1021441
43.
RAC1P29S Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance · 2019
No notice
44.
Long G.V., Fung C., Menzies A.M., Pupo G.M., Carlino M.S., Hyman J., Shahheydari H., Tembe V., Thompson J.F., Saw R.P., et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat. Commun. 2014;5:5694.
Not in our library10.1038/ncomms6694
45.
Misek S.A., Appleton K.M., Dexheimer T.S., Lisabeth E.M., Lo R.S., Larsen S.D., Gallo K.A., Neubig R.R. Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells. Oncogene. 2020;39:1466-1483.
Not in our library10.1038/s41388-019-1074-1
46.
Molnar E., Garay T., Donia M., Baranyi M., Rittler D., Berger W., Timar J., Grusch M., Hegedus B. Long-Term Vemurafenib Exposure Induced Alterations of Cell Phenotypes in Melanoma: Increased Cell Migration and Its Association with EGFR Expression. Int. J. Mol. Sci. 2019;20:4484.
Not in our library10.3390/ijms20184484
47.
Monsma D.J., Cherba D.M., Eugster E.E., Dylewski D.L., Davidson P.T., Peterson C.A., Borgman A.S., Winn M.E., Dykema K.J., Webb C.P., et al. Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms. Am. J. Cancer Res. 2015;5:1507-1518.
Not in our library
48.
Muller J., Krijgsman O., Tsoi J., Robert L., Hugo W., Song C., Kong X., Possik P.A., Cornelissen-Steijger P.D., Geukes Foppen M.H., et al. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat. Commun. 2014;5:5712.
Not in our library10.1038/ncomms6712
49.
Nazarian R., Shi H., Wang Q., Kong X., Koya R.C., Lee H., Chen Z., Lee M.K., Attar N., Sazegar H., et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973-977.
Not in our library10.1038/nature09626
50.
Poulikakos P.I., Persaud Y., Janakiraman M., Kong X., Ng C., Moriceau G., Shi H., Atefi M., Titz B., Gabay M.T., et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480:387-390.
Not in our library10.1038/nature10662
51.
Rizos H., Menzies A.M., Pupo G.M., Carlino M.S., Fung C., Hyman J., Haydu L.E., Mijatov B., Becker T.M., Boyd S.C., et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: Spectrum and clinical impact. Clin. Cancer Res. 2014;20:1965-1977.
Not in our library10.1158/1078-0432.ccr-13-3122
52.
Ruggiero C.F., Malpicci D., Fattore L., Madonna G., Vanella V., Mallardo D., Liguoro D., Salvati V., Capone M., Bedogni B., et al. ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin. Cancers. 2019;11:1425.
Not in our library10.3390/cancers11101425
53.
Sabbatino F., Wang Y., Wang X., Flaherty K.T., Yu L., Pepin D., Scognamiglio G., Pepe S., Kirkwood J.M., Cooper Z.A., et al. PDGFRα up-regulation mediated by sonic hedgehog pathway activation leads to BRAF inhibitor resistance in melanoma cells with BRAF mutation. Oncotarget. 2014;5:1926-1941.
Not in our library10.18632/oncotarget.1878
54.
Shen C.H., Kim S.H., Trousil S., Frederick D.T., Piris A., Yuan P., Cai L., Gu L., Li M., Lee J.H., et al. Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. Nat. Med. 2016;22:1056-1061.
Not in our library10.1038/nm.4155
55.
Shi H., Hong A., Kong X., Koya R.C., Song C., Moriceau G., Hugo W., Yu C.C., Ng C., Chodon T., et al. A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov. 2014;4:69-79.
Not in our library10.1158/2159-8290.cd-13-0279
56.
Shull A.Y., Latham-Schwark A., Ramasamy P., Leskoske K., Oroian D., Birtwistle M.R., Buckhaults P.J. Novel somatic mutations to PI3K pathway genes in metastatic melanoma. PLoS ONE. 2012;7:e43369.
Not in our library10.1371/journal.pone.0043369
57.
Straussman R., Morikawa T., Shee K., Barzily-Rokni M., Qian Z.R., Du J., Davis A., Mongare M.M., Gould J., Frederick D.T., et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500-504.
Not in our library10.1038/nature11183
58.
Sun C., Wang L., Huang S., Heynen G.J., Prahallad A., Robert C., Haanen J., Blank C., Wesseling J., Willems S.M., et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014;508:118-122.
Not in our library10.1038/nature13121
59.
Sun X., Li J., Sun Y., Zhang Y., Dong L., Shen C., Yang L., Yang M., Li Y., Shen G., et al. miR-7 reverses the resistance to BRAFi in melanoma by targeting EGFR/IGF-1R/CRAF and inhibiting the MAPK and PI3K/AKT signaling pathways. Oncotarget. 2016;7:53558-53570.
Not in our library10.18632/oncotarget.10669
60.
Teh J.L.F., Cheng P.F., Purwin T.J., Nikbakht N., Patel P., Chervoneva I., Ertel A., Fortina P.M., Kleiber I., HooKim K., et al. In Vivo E2F Reporting Reveals Efficacious Schedules of MEK1/2-CDK4/6 Targeting and mTOR-S6 Resistance Mechanisms. Cancer Discov. 2018;8:568-581.
Not in our library10.1158/2159-8290.cd-17-0699
61.
Van Allen E.M., Wagle N., Sucker A., Treacy D.J., Johannessen C.M., Goetz E.M., Place C.S., Taylor-Weiner A., Whittaker S., Kryukov G.V., et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014;4:94-109.
Not in our library10.1158/2159-8290.cd-13-0617
62.
Villanueva J., Infante J.R., Krepler C., Reyes-Uribe P., Samanta M., Chen H.Y., Li B., Swoboda R.K., Wilson M., Vultur A., et al. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep. 2013;4:1090-1099.
Not in our library10.1016/j.celrep.2013.08.023
63.
Wagenaar T.R., Ma L., Roscoe B., Park S.M., Bolon D.N., Green M.R. Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain. Pigment Cell Melanoma Res. 2014;27:124-133.
Not in our library10.1111/pcmr.12171
64.
A transcriptional MAPK Pathway Activity Score (MPAS) is a clinically relevant biomarker in multiple cancer types · 2018
No notice
65.
Watson I.R., Li L., Cabeceiras P.K., Mahdavi M., Gutschner T., Genovese G., Wang G., Fang Z., Tepper J.M., Stemke-Hale K., et al. The RAC1 P29S hotspot mutation in melanoma confers resistance to pharmacological inhibition of RAF. Cancer Res. 2014;74:4845-4852.
Not in our library10.1158/0008-5472.can-14-1232-t
66.
Xue G., Kohler R., Tang F., Hynx D., Wang Y., Orso F., Pretre V., Ritschard R., Hirschmann P., Cron P., et al. mTORC1/autophagy-regulated MerTK in mutant BRAFV600 melanoma with acquired resistance to BRAF inhibition. Oncotarget. 2017;8:69204-69218.
Not in our library10.18632/oncotarget.18213
67.
Yadav V., Zhang X., Liu J., Estrem S., Li S., Gong X.Q., Buchanan S., Henry J.R., Starling J.J., Peng S.B. Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J. Biol. Chem. 2012;287:28087-28098.
Not in our library10.1074/jbc.m112.377218
68.
Perna D., Karreth F.A., Rust A.G., Perez-Mancera P.A., Rashid M., Iorio F., Alifrangis C., Arends M.J., Bosenberg M.W., Bollag G., et al. BRAF inhibitor resistance mediated by the AKT pathway in an oncogenic BRAF mouse melanoma model. Proc. Natl. Acad. Sci. USA. 2015;112:E536-E545.
Not in our library10.1073/pnas.1418163112
69.
Hoogstraat M., Gadellaa-van Hooijdonk C.G., Ubink I., Besselink N.J., Pieterse M., Veldhuis W., van Stralen M., Meijer E.F., Willems S.M., Hadders M.A., et al. Detailed imaging and genetic analysis reveal a secondary BRAF(L505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib. Pigment Cell Melanoma Res. 2015;28:318-323.
Not in our library10.1111/pcmr.12347
70.
Pupo G.M., Boyd S.C., Fung C., Carlino M.S., Menzies A.M., Pedersen B., Johansson P., Hayward N.K., Kefford R.F., Scolyer R.A., et al. Clinical significance of intronic variants in BRAF inhibitor resistant melanomas with altered BRAF transcript splicing. Biomark. Res. 2017;5:17.
Not in our library10.1186/s40364-017-0098-3
71.
Shi H., Moriceau G., Kong X., Lee M.K., Lee H., Koya R.C., Ng C., Chodon T., Scolyer R.A., Dahlman K.B., et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat. Commun. 2012;3:724.
Not in our library10.1038/ncomms1727
72.
Johnson G.L., Stuhlmiller T.J., Angus S.P., Zawistowski J.S., Graves L.M. Molecular pathways: Adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer. Clin. Cancer Res. 2014;20:2516-2522.
Not in our library10.1158/1078-0432.ccr-13-1081
73.
Mistry H.B., Orrell D., Eftimie R. Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma. Cancer Chemother. Pharmacol. 2018;81:325-332.
Not in our library10.1007/s00280-017-3486-3
74.
Molina-Arcas M., Downward J. How to fool a wonder drug: Truncate and dimerize. Cancer Cell. 2012;21:7-9.
Not in our library10.1016/j.ccr.2011.12.017
75.
Benito-Jardon L., Diaz-Martinez M., Arellano-Sanchez N., Vaquero-Morales P., Esparis-Ogando A., Teixido J. Resistance to MAPK Inhibitors in Melanoma Involves Activation of the IGF1R-MEK5-Erk5 Pathway. Cancer Res. 2019;79:2244-2256.
Not in our library10.1158/0008-5472.can-18-2762
76.
Goetz E.M., Garraway L.A. Mechanisms of Resistance to Mitogen-Activated Protein Kinase Pathway Inhibition in BRAF-Mutant Melanoma. Am. Soc. Clin. Oncol. Educ. Book. 2012;32:680-684.
Not in our library10.14694/edbook_am.2012.32.189
77.
Lidsky M., Antoun G., Speicher P., Adams B., Turley R., Augustine C., Tyler D., Ali-Osman F. Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells. J. Biol. Chem. 2014;289:27714-27726.
Not in our library10.1074/jbc.m113.532432
78.
Tanda E.T., Vanni I., Boutros A., Andreotti V., Bruno W., Ghiorzo P., Spagnolo F. Current state of target treatment in BRAF mutated melanoma. Front. Mol. Biosci. 2020;7:154.
Not in our library10.3389/fmolb.2020.00154
79.
Paraiso K.H., Xiang Y., Rebecca V.W., Abel E.V., Chen Y.A., Munko A.C., Wood E., Fedorenko I.V., Sondak V.K., Anderson A.R., et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 2011;71:2750-2760.
Not in our library10.1158/0008-5472.can-10-2954
80.
Ahn J.H., Lee M. Autophagy-Dependent Survival of Mutant B-Raf Melanoma Cells Selected for Resistance to Apoptosis Induced by Inhibitors against Oncogenic B-Raf. Biomol. Ther. 2013;21:114-120.
Not in our library10.4062/biomolther.2013.012
81.
Transcriptional regulation of autophagy-lysosomal function in BRAF-driven melanoma progression and chemoresistance · 2019
No notice
82.
Martin S., Dudek-Peric A.M., Garg A.D., Roose H., Demirsoy S., Van Eygen S., Mertens F., Vangheluwe P., Vankelecom H., Agostinis P. An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells. Autophagy. 2017;13:1512-1527.
Not in our library10.1080/15548627.2017.1332550
83.
Ma X.H., Piao S.F., Dey S., McAfee Q., Karakousis G., Villanueva J., Hart L.S., Levi S., Hu J., Zhang G., et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J. Clin. Investig. 2014;124:1406-1417.
Not in our library10.1172/jci70454
84.
Szasz I., Koroknai V., Kiss T., Vizkeleti L., Adany R., Balazs M. Molecular alterations associated with acquired resistance to BRAFV600E targeted therapy in melanoma cells. Melanoma Res. 2019;29:390-400.
Not in our library10.1097/cmr.0000000000000588
85.
Wang J., Sinnberg T., Niessner H., Dolker R., Sauer B., Kempf W.E., Meier F., Leslie N., Schittek B. PTEN regulates IGF-1R-mediated therapy resistance in melanoma. Pigment Cell Melanoma Res. 2015;28:572-589.
Not in our library10.1111/pcmr.12390
86.
Wilson T.R., Fridlyand J., Yan Y., Penuel E., Burton L., Chan E., Peng J., Lin E., Wang Y., Sosman J., et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487:505-509.
Not in our library10.1038/nature11249
87.
Miller M.A., Oudin M.J., Sullivan R.J., Wang S.J., Meyer A.S., Im H., Frederick D.T., Tadros J., Griffith L.G., Lee H., et al. Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance. Cancer Discov. 2016;6:382-399.
Not in our library10.1158/2159-8290.cd-15-0933
88.
Ahn J.H., Hwang S.H., Cho H.S., Lee M. Differential Gene Expression Common to Acquired and Intrinsic Resistance to BRAF Inhibitor Revealed by RNA-Seq Analysis. Biomol. Ther. 2019;27:302-310.
Not in our library10.4062/biomolther.2018.133
89.
A novel chalcone derivative has antitumor activity in melanoma by inducing DNA damage through the upregulation of ROS products · 2020
Not checked
90.
Martin C.A., Cullinane C., Kirby L., Abuhammad S., Lelliott E.J., Waldeck K., Young R.J., Brajanovski N., Cameron D.P., Walker R., et al. Palbociclib synergizes with BRAF and MEK inhibitors in treatment naive melanoma but not after the development of BRAF inhibitor resistance. Int. J. Cancer. 2018;142:2139-2152.
Not in our library10.1002/ijc.31220
91.
Functional Genomic Screening Independently Identifies CUL3 as a Mediator of Vemurafenib Resistance via Src-Rac1 Signaling Axis · 2020
Not checked
92.
Whittaker S.R., Theurillat J.P., Van Allen E., Wagle N., Hsiao J., Cowley G.S., Schadendorf D., Root D.E., Garraway L.A. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 2013;3:350-362.
Not in our library10.1158/2159-8290.cd-12-0470
93.
Rac and Rho GTPases in cancer cell motility control · 2010
No notice
94.
Kim M.H., Kim J., Hong H., Lee S.H., Lee J.K., Jung E., Kim J. Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 2016;35:462-478.
Not in our library10.15252/embj.201592081
95.
Fisher M.L., Grun D., Adhikary G., Xu W., Eckert R.L. Inhibition of YAP function overcomes BRAF inhibitor resistance in melanoma cancer stem cells. Oncotarget. 2017;8:110257-110272.
Not in our library10.18632/oncotarget.22628
96.
Schmitt M., Sinnberg T., Nalpas N.C., Maass A., Schittek B., Macek B. Quantitative Proteomics Links the Intermediate Filament Nestin to Resistance to Targeted BRAF Inhibition in Melanoma Cells. Mol. Cell. Proteom. 2019;18:1096-1109.
Not in our library10.1074/mcp.ra119.001302
97.
Titz B., Lomova A., Le A., Hugo W., Kong X., Hoeve J.T., Friedman M., Shi H., Moriceau G., Song C., et al. JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma. Cell Discov. 2016;2:16028.
Not in our library10.1038/celldisc.2016.28
98.
Cordaro F.G., De Presbiteris A.L., Camerlingo R., Mozzillo N., Pirozzi G., Cavalcanti E., Manca A., Palmieri G., Cossu A., Ciliberto G., et al. Phenotype characterization of human melanoma cells resistant to dabrafenib. Oncol. Rep. 2017;38:2741-2751.
Not in our library10.3892/or.2017.5963
99.
Wang J., Huang S.K., Marzese D.M., Hsu S.C., Kawas N.P., Chong K.K., Long G.V., Menzies A.M., Scolyer R.A., Izraely S., et al. Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas. J. Investig. Dermatol. 2015;135:532-541.
Not in our library10.1038/jid.2014.418
100.
The Epithelial-to-Mesenchymal Transition in Cancer · 2018
No notice
101.
Seip K., Fleten K.G., Barkovskaya A., Nygaard V., Haugen M.H., Engesaeter B.O., Maelandsmo G.M., Prasmickaite L. Fibroblast-induced switching to the mesenchymal-like phenotype and PI3K/mTOR signaling protects melanoma cells from BRAF inhibitors. Oncotarget. 2016;7:19997-20015.
Not in our library10.18632/oncotarget.7671
102.
Smith M.P., Wellbrock C. Molecular Pathways: Maintaining MAPK Inhibitor Sensitivity by Targeting Nonmutational Tolerance. Clin. Cancer Res. 2016;22:5966-5970.
Not in our library10.1158/1078-0432.ccr-16-0954
103.
Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells · 2015
No notice
104.
Osrodek M., Hartman M.L., Czyz M. Physiologically Relevant Oxygen Concentration (6% O2) as an Important Component of the Microenvironment Impacting Melanoma Phenotype and Melanoma Response to Targeted Therapeutics In Vitro. Int. J. Mol. Sci. 2019;20:4203.
Not in our library10.3390/ijms20174203
105.
Aloia A., Mullhaupt D., Chabbert C.D., Eberhart T., Fluckiger-Mangual S., Vukolic A., Eichhoff O., Irmisch A., Alexander L.T., Scibona E., et al. A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors. Clin. Cancer Res. 2019;25:6852-6867.
Not in our library10.1158/1078-0432.ccr-19-0253
106.
Audrito V., Manago A., La Vecchia S., Zamporlini F., Vitale N., Baroni G., Cignetto S., Serra S., Bologna C., Stingi A., et al. Nicotinamide Phosphoribosyltransferase (NAMPT) as a Therapeutic Target in BRAF-Mutated Metastatic Melanoma. J. Natl. Cancer Inst. 2018;110:290-303.
Not in our library10.1093/jnci/djx198
107.
Corazao-Rozas P., Guerreschi P., Andre F., Gabert P.E., Lancel S., Dekiouk S., Fontaine D., Tardivel M., Savina A., Quesnel B., et al. Mitochondrial oxidative phosphorylation controls cancer cell’s life and death decisions upon exposure to MAPK inhibitors. Oncotarget. 2016;7:39473-39485.
Not in our library10.18632/oncotarget.7790
108.
Mitochondrial oxidative stress is the achille's heel of melanoma cells resistant to Braf-mutant inhibitor · 2013
No notice
109.
Figarola J.L., Singhal J., Singhal S., Kusari J., Riggs A. Bioenergetic modulation with the mitochondria uncouplers SR4 and niclosamide prevents proliferation and growth of treatment-naive and vemurafenib-resistant melanomas. Oncotarget. 2018;9:36945-36965.
Not in our library10.18632/oncotarget.26421
110.
Su Y., Bintz M., Yang Y., Robert L., Ng A.H.C., Liu V., Ribas A., Heath J.R., Wei W. Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance. PLoS Comput. Biol. 2019;15:e1007034.
Not in our library10.1371/journal.pcbi.1007034
111.
Wang L., de Oliveira R.L., Huijberts S., Bosdriesz E., Pencheva N., Brunen D., Bosma A., Song J.Y., Zevenhoven J., Los-de Vries G.T., et al. An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential. Cell. 2018;173:1413-1425.e1414.
Not in our library10.1016/j.cell.2018.04.012
112.
Pan M., Reid M.A., Lowman X.H., Kulkarni R.P., Tran T.Q., Liu X., Yang Y., Hernandez-Davies J.E., Rosales K.K., Li H., et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat. Cell Biol. 2016;18:1090-1101.
Not in our library10.1038/ncb3410
113.
Liu X., Zhang S.M., McGeary M.K., Krykbaeva I., Lai L., Jansen D.J., Kales S.C., Simeonov A., Hall M.D., Kelly D.P., et al. KDM5B Promotes Drug Resistance by Regulating Melanoma-Propagating Cell Subpopulations. Mol. Cancer Ther. 2019;18:706-717.
Not in our library10.1158/1535-7163.mct-18-0395
114.
Bajpe P.K., Prahallad A., Horlings H., Nagtegaal I., Beijersbergen R., Bernards R. A chromatin modifier genetic screen identifies SIRT2 as a modulator of response to targeted therapies through the regulation of MEK kinase activity. Oncogene. 2015;34:531-536.
Not in our library10.1038/onc.2013.588
115.
Strub T., Ghiraldini F.G., Carcamo S., Li M., Wroblewska A., Singh R., Goldberg M.S., Hasson D., Wang Z., Gallagher S.J., et al. SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signalling. Nat. Commun. 2018;9:3440.
Not in our library10.1038/s41467-018-05966-z
116.
Bugide S., Parajuli K.R., Chava S., Pattanayak R., Manna D.L.D., Shrestha D., Yang E.S., Cai G., Johnson D.B., Gupta R. Loss of HAT1 expression confers BRAFV600E inhibitor resistance to melanoma cells by activating MAPK signaling via IGF1R. Oncogenesis. 2020;9:44.
Not in our library10.1038/s41389-020-0228-x
117.
Emmons M.F., Faiao-Flores F., Sharma R., Thapa R., Messina J.L., Becker J.C., Schadendorf D., Seto E., Sondak V.K., Koomen J.M., et al. HDAC8 Regulates a Stress Response Pathway in Melanoma to Mediate Escape from BRAF Inhibitor Therapy. Cancer Res. 2019;79:2947-2961.
Not in our library10.1158/0008-5472.can-19-0040
118.
Sanjana N.E., Wright J., Zheng K., Shalem O., Fontanillas P., Joung J., Cheng C., Regev A., Zhang F. High-resolution interrogation of functional elements in the noncoding genome. Science. 2016;353:1545-1549.
Not in our library10.1126/science.aaf7613
119.
Joung J., Engreitz J.M., Konermann S., Abudayyeh O.O., Verdine V.K., Aguet F., Gootenberg J.S., Sanjana N.E., Wright J.B., Fulco C.P., et al. Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood. Nature. 2017;548:343-346.
Not in our library10.1038/nature23451
120.
Atkinson J.M., Rank K.B., Zeng Y., Capen A., Yadav V., Manro J.R., Engler T.A., Chedid M. Activating the Wnt/beta-Catenin Pathway for the Treatment of Melanoma--Application of LY2090314, a Novel Selective Inhibitor of Glycogen Synthase Kinase-3. PLoS ONE. 2015;10:e0125028.
Not in our library10.1371/journal.pone.0125028
121.
Azimi A., Tuominen R., Svedman F.C., Caramuta S., Pernemalm M., Frostvik Stolt M., Kanter L., Kharaziha P., Lehtio J., Hertzman Johansson C., et al. Silencing FLI or targeting CD13/ANPEP lead to dephosphorylation of EPHA2, a mediator of BRAF inhibitor resistance, and induce growth arrest or apoptosis in melanoma cells. Cell Death Dis. 2017;8:e3029.
Not in our library10.1038/cddis.2017.406
122.
Becker T.M., Boyd S.C., Mijatov B., Gowrishankar K., Snoyman S., Pupo G.M., Scolyer R.A., Mann G.J., Kefford R.F., Zhang X.D., et al. Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene. 2014;33:1158-1166.
Not in our library10.1038/onc.2013.45
123.
Boregowda R.K., Medina D.J., Markert E., Bryan M.A., Chen W., Chen S., Rabkin A., Vido M.J., Gunderson S.I., Chekmareva M., et al. The transcription factor RUNX2 regulates receptor tyrosine kinase expression in melanoma. Oncotarget. 2016;7:29689-29707.
Not in our library10.18632/oncotarget.8822
124.
Chien A.J., Haydu L.E., Biechele T.L., Kulikauskas R.M., Rizos H., Kefford R.F., Scolyer R.A., Moon R.T., Long G.V. Targeted BRAF inhibition impacts survival in melanoma patients with high levels of Wnt/beta-catenin signaling. PLoS ONE. 2014;9:e94748.
Not in our library10.1371/journal.pone.0094748
125.
Corre S., Tardif N., Mouchet N., Leclair H.M., Boussemart L., Gautron A., Bachelot L., Perrot A., Soshilov A., Rogiers A., et al. Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. Nat. Commun. 2018;9:4775.
Not in our library10.1038/s41467-018-06951-2
126.
Cronin J.C., Loftus S.K., Baxter L.L., Swatkoski S., Gucek M., Pavan W.J. Identification and functional analysis of SOX10 phosphorylation sites in melanoma. PLoS ONE. 2018;13:e0190834.
Not in our library10.1371/journal.pone.0190834
127.
Czyz M., Sztiller-Sikorska M., Gajos-Michniewicz A., Osrodek M., Hartman M.L. Plasticity of Drug-Naive and Vemurafenib- or Trametinib-Resistant Melanoma Cells in Execution of Differentiation/Pigmentation Program. J. Oncol. Print. 2019;2019:1697913.
Not in our library10.1155/2019/1697913
128.
Delmas A., Cherier J., Pohorecka M., Medale-Giamarchi C., Meyer N., Casanova A., Sordet O., Lamant L., Savina A., Pradines A., et al. The c-Jun/RHOB/AKT pathway confers resistance of BRAF-mutant melanoma cells to MAPK inhibitors. Oncotarget. 2015;6:15250-15264.
Not in our library10.18632/oncotarget.3888
129.
Giricz O., Mo Y., Dahlman K.B., Cotto-Rios X.M., Vardabasso C., Nguyen H., Matusow B., Bartenstein M., Polishchuk V., Johnson D.B., et al. The RUNX1/IL-34/CSF-1R axis is an autocrinally regulated modulator of resistance to BRAF-V600E inhibition in melanoma. JCI Insight. 2018;3:26.
Not in our library10.1172/jci.insight.120422
130.
Hartman M.L., Sztiller-Sikorska M., Gajos-Michniewicz A., Czyz M. Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity. Cells. 2020;9:142.
Not in our library10.3390/cells9010142
131.
Huser L., Sachindra S., Granados K., Federico A., Larribere L., Novak D., Umansky V., Altevogt P., Utikal J. SOX2-mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma. Int. J. Cancer. 2018;143:3131-3142.
Not in our library10.1002/ijc.31609
132.
Ji Z., Chen Y.E., Kumar R., Taylor M., Njauw C.N.J., Miao B., Frederick D.T., Wargo J.A., Flaherty K.T., Tsao H., et al. MITF Modulates Therapeutic Resistance through EGFR Signaling. J. Investig. Dermatol. 2015;135:1863-1872.
Not in our library10.1038/jid.2015.105
133.
Liu F., Jiang C.C., Yan X.G., Tseng H.Y., Wang C.Y., Zhang Y.Y., Yari H., La T., Farrelly M., Guo S.T., et al. BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma. Oncotarget. 2017;8:69477-69492.
Not in our library10.18632/oncotarget.17704
134.
Mohapatra P., Prasad C.P., Andersson T. Combination therapy targeting the elevated interleukin-6 level reduces invasive migration of BRAF inhibitor-resistant melanoma cells. Mol. Oncol. 2019;13:480-494.
Not in our library10.1002/1878-0261.12433
135.
Perotti V., Baldassari P., Molla A., Nicolini G., Bersani I., Grazia G., Benigni F., Maurichi A., Santinami M., Anichini A., et al. An actionable axis linking NFATc2 to EZH2 controls the EMT-like program of melanoma cells. Oncogene. 2019;38:4384-4396.
Not in our library10.1038/s41388-019-0729-2
136.
Ramsdale R., Jorissen R.N., Li F.Z., Al-Obaidi S., Ward T., Sheppard K.E., Bukczynska P.E., Young R.J., Boyle S.E., Shackleton M., et al. The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma. Sci. Signal. 2015;8:ra82.
Not in our library10.1126/scisignal.aab1111
137.
ZEB1‐mediated melanoma cell plasticity enhances resistance to MAPK inhibitors · 2016
No notice
138.
Singleton K.R., Crawford L., Tsui E., Manchester H.E., Maertens O., Liu X., Liberti M.V., Magpusao A.N., Stein E.M., Tingley J.P., et al. Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence. Cell Rep. 2017;21:2796-2812.
Not in our library10.1016/j.celrep.2017.11.022
139.
A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib · 2016
Not checked
140.
Liu X., Mi J., Qin H., Li Z., Chai J., Li M., Wu J., Xu J. E2F1/IGF-1R Loop Contributes to BRAF Inhibitor Resistance in Melanoma. J. Investig. Dermatol. 2020;140:1295-1299.e1291.
Not in our library10.1016/j.jid.2019.09.025
141.
Zecena H., Tveit D., Wang Z., Farhat A., Panchal P., Liu J., Singh S.J., Sanghera A., Bainiwal A., Teo S.Y., et al. Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma. BMC Syst. Biol. 2018;12:33.
Not in our library10.1186/s12918-018-0554-1
142.
Fofaria N.M., Frederick D.T., Sullivan R.J., Flaherty K.T., Srivastava S.K. Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma. Oncotarget. 2015;6:40535-40556.
Not in our library10.18632/oncotarget.5755
143.
Fernandez M., Sutterluty-Fall H., Schwarzler C., Lemeille S., Boehncke W.H., Merat R. Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition. Cancer Med. 2017;6:1652-1664.
Not in our library10.1002/cam4.1091
144.
Zhan Y., Dahabieh M.S., Rajakumar A., Dobocan M.C., M’Boutchou M.N., Goncalves C., Lucy S.L., Pettersson F., Topisirovic I., van Kempen L., et al. The role of eIF4E in response and acquired resistance to vemurafenib in melanoma. J. Investig. Dermatol. 2015;135:1368-1376.
Not in our library10.1038/jid.2015.11
145.
Boussemart L., Malka-Mahieu H., Girault I., Allard D., Hemmingsson O., Tomasic G., Thomas M., Basmadjian C., Ribeiro N., Thuaud F., et al. eIF4F is a nexus of resistance to anti-BRAF and anti-MEK cancer therapies. Nature. 2014;513:105-109.
Not in our library10.1038/nature13572
146.
Caporali S., Amaro A., Levati L., Alvino E., Lacal P.M., Mastroeni S., Ruffini F., Bonmassar L., Cappellini G.C.A., Felli N., et al. miR-126-3p down-regulation contributes to dabrafenib acquired resistance in melanoma by up-regulating ADAM9 and VEGF-A. J. Exp. Clin. Cancer Res. 2019;38:272.
Not in our library10.1186/s13046-019-1238-4
147.
Diaz-Martinez M., Benito-Jardon L., Alonso L., Koetz-Ploch L., Hernando E., Teixido J. miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma. Cancer Res. 2018;78:1017-1030.
Not in our library10.1158/0008-5472.can-17-1318
148.
Fattore L., Mancini R., Acunzo M., Romano G., Lagana A., Pisanu M.E., Malpicci D., Madonna G., Mallardo D., Capone M., et al. miR-579-3p controls melanoma progression and resistance to target therapy. Proc. Natl. Acad. Sci. USA. 2016;113:E5005-E5013.
Not in our library10.1073/pnas.1607753113
149.
Fattore L., Ruggiero C.F., Pisanu M.E., Liguoro D., Cerri A., Costantini S., Capone F., Acunzo M., Romano G., Nigita G., et al. Reprogramming miRNAs global expression orchestrates development of drug resistance in BRAF mutated melanoma. Cell Death Differ. 2019;26:1267-1282.
Not in our library10.1038/s41418-018-0205-5
150.
Hwang S.H., Ahn J.H., Lee M. Upregulation of S100A9 contributes to the acquired resistance to BRAF inhibitors. Genes Genom. 2019;41:1273-1280.
Not in our library10.1007/s13258-019-00856-0
151.
Kim J.H., Ahn J.H., Lee M. Upregulation of MicroRNA-1246 Is Associated with BRAF Inhibitor Resistance in Melanoma Cells with Mutant BRAF. Cancer Res. Treat. 2017;49:947-959.
Not in our library10.4143/crt.2016.280
152.
Kozar I., Cesi G., Margue C., Philippidou D., Kreis S. Impact of BRAF kinase inhibitors on the miRNomes and transcriptomes of melanoma cells. Biochim. Biophys. Acta Gen. Subj. 2017;1861:2980-2992.
Not in our library10.1016/j.bbagen.2017.04.005
153.
Liu S., Tetzlaff M.T., Wang T., Yang R., Xie L., Zhang G., Krepler C., Xiao M., Beqiri M., Xu W., et al. miR-200c/Bmi1 axis and epithelial-mesenchymal transition contribute to acquired resistance to BRAF inhibitor treatment. Pigment Cell Melanoma Res. 2015;28:431-441.
Not in our library10.1111/pcmr.12379
154.
Stark M.S., Bonazzi V.F., Boyle G.M., Palmer J.M., Symmons J., Lanagan C.M., Schmidt C.W., Herington A.C., Ballotti R., Pollock P.M., et al. miR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma. Oncotarget. 2015;6:17753-17763.
Not in our library10.18632/oncotarget.3924
155.
Rapino F., Delaunay S., Rambow F., Zhou Z., Tharun L., De Tullio P., Sin O., Shostak K., Schmitz S., Piepers J., et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature. 2018;558:605-609.
Not in our library10.1038/s41586-018-0243-7
156.
Frederick D.T., Piris A., Cogdill A.P., Cooper Z.A., Lezcano C., Ferrone C.R., Mitra D., Boni A., Newton L.P., Liu C., et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 2013;19:1225-1231.
Not in our library10.1158/1078-0432.ccr-12-1630
157.
Hopkins A.M., Van Dyk M., Rowland A., Sorich M.J. Effect of early adverse events on response and survival outcomes of advanced melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib: A pooled analysis of clinical trial data. Pigment Cell Melanoma Res. 2019;32:576-583.
Not in our library10.1111/pcmr.12773
158.
Ben-Betzalel G., Baruch E.N., Boursi B., Steinberg-Silman Y., Asher N., Shapira-Frommer R., Schachter J., Markel G. Possible immune adverse events as predictors of durable response to BRAF inhibitors in patients with BRAF V600-mutant metastatic melanoma. Eur. J. Cancer. 2018;101:229-235.
Not in our library10.1016/j.ejca.2018.06.030
159.
Panniculitis and vitiligo occurring during BRAF and MEK inhibitors combination in advanced melanoma patients: Potential predictive role of treatment efficacy. · 2019
Not checked
160.
Bellmann L., Cappellano G., Schachtl-Riess J.F., Prokopi A., Seretis A., Ortner D., Tripp C.H., Brinckerhoff C.E., Mullins D.W., Stoitzner P. A TLR7 agonist strengthens T and NK cell function during BRAF-targeted therapy in a preclinical melanoma model. Int. J. Cancer. 2020;146:1409-1420.
Not in our library10.1002/ijc.32777
161.
Greenplate A.R., McClanahan D.D., Oberholtzer B.K., Doxie D.B., Roe C.E., Diggins K.E., Leelatian N., Rasmussen M.L., Kelley M.C., Gama V., et al. Computational Immune Monitoring Reveals Abnormal Double-Negative T Cells Present across Human Tumor Types. Cancer Immunol. Res. 2019;7:86-99.
Not in our library10.1158/2326-6066.cir-17-0692
162.
Steinberg S.M., Shabaneh T.B., Zhang P., Martyanov V., Li Z., Malik B.T., Wood T.A., Boni A., Molodtsov A., Angeles C.V., et al. Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors. Cancer Res. 2017;77:1599-1610.
Not in our library10.1158/0008-5472.can-16-1755
163.
Jazirehi A.R., Nazarian R., Torres-Collado A.X., Economou J.S. Aberrant apoptotic machinery confers melanoma dual resistance to BRAF(V600E) inhibitor and immune effector cells: Immunosensitization by a histone deacetylase inhibitor. Am. J. Clin. Exp. Immunol. 2014;3:43-56.
Not in our library
164.
Pieper N., Zaremba A., Leonardelli S., Harbers F.N., Schwamborn M., Lubcke S., Schrors B., Baingo J., Schramm A., Haferkamp S., et al. Evolution of melanoma cross-resistance to CD8+ T cells and MAPK inhibition in the course of BRAFi treatment. Oncoimmunology. 2018;7:e1450127.
Not in our library10.1080/2162402x.2018.1450127
165.
Atefi M., Avramis E., Lassen A., Wong D.J., Robert L., Foulad D., Cerniglia M., Titz B., Chodon T., Graeber T.G., et al. Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma. Clin. Cancer Res. 2014;20:3446-3457.
Not in our library10.1158/1078-0432.ccr-13-2797
166.
Inducible but Not Constitutive Expression of PD-L1 in Human Melanoma Cells Is Dependent on Activation of NF-κB · 2015
No notice
167.
Jiang X., Zhou J., Giobbie-Hurder A., Wargo J., Hodi F.S. The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD-L1 expression that is reversible by MEK and PI3K inhibition. Clin. Cancer Res. 2013;19:598-609.
Not in our library10.1158/1078-0432.ccr-12-2731
168.
Kim M.H., Kim C.G., Kim S.K., Shin S.J., Choe E.A., Park S.H., Shin E.C., Kim J. YAP-Induced PD-L1 Expression Drives Immune Evasion in BRAFi-Resistant Melanoma. Cancer Immunol. Res. 2018;6:255-266.
Not in our library10.1158/2326-6066.cir-17-0320
169.
Sottile R., Pangigadde P.N., Tan T., Anichini A., Sabbatino F., Trecroci F., Favoino E., Orgiano L., Roberts J., Ferrone S., et al. HLA class I downregulation is associated with enhanced NK-cell killing of melanoma cells with acquired drug resistance to BRAF inhibitors. Eur. J. Immunol. 2016;46:409-419.
Not in our library10.1002/eji.201445289
170.
BRAF inhibition curtails IFN‐gamma‐inducible PD‐L1 expression and upregulates the immunoregulatory protein galectin‐1 in melanoma cells · 2020
Not checked
171.
Atay C., Kwak T., Lavilla-Alonso S., Donthireddy L., Richards A., Moberg V., Pilon-Thomas S., Schell M., Messina J.L., Rebecca V.W., et al. BRAF Targeting Sensitizes Resistant Melanoma to Cytotoxic T Cells. Clin. Cancer Res. 2019;25:2783-2794.
Not in our library10.1158/1078-0432.ccr-18-2725
172.
Beauchemin N., Arabzadeh A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev. 2013;32:643-671.
Not in our library10.1007/s10555-013-9444-6
173.
Turcu G., Nedelcu R.I., Ion D.A., Brinzea A., Cioplea M.D., Jilaveanu L.B., Zurac S.A. CEACAM1: Expression and Role in Melanocyte Transformation. Dis. Markers. 2016;2016:9406319.
Not in our library10.1155/2016/9406319
174.
Kfir-Elirachman K., Ortenberg R., Vizel B., Besser M.J., Barshack I., Schachter J., Nemlich Y., Markel G. Regulation of CEACAM1 Protein Expression by the Transcription Factor ETS-1 in BRAF-Mutant Human Metastatic Melanoma Cells. Neoplasia. 2018;20:401-409.
Not in our library10.1016/j.neo.2018.01.012
175.
Mandala M., Massi D. Immunotolerance as a Mechanism of Resistance to Targeted Therapies in Melanoma. Handb. Exp. Pharmacol. 2018;249:129-143.
Not in our library10.1007/164_2017_5
176.
Wang T., Xiao M., Ge Y., Krepler C., Belser E., Lopez-Coral A., Xu X., Zhang G., Azuma R., Liu Q., et al. BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth. Clin. Cancer Res. 2015;21:1652-1664.
Not in our library10.1158/1078-0432.ccr-14-1554
177.
Abdel-Rahman O., ElHalawani H., Ahmed H. Doublet BRAF/MEK inhibition versus single-agent BRAF inhibition in the management of BRAF-mutant advanced melanoma, biological rationale and meta-analysis of published data. Clin. Transl. Oncol. 2016;18:848-858.
Not in our library10.1007/s12094-015-1438-0
178.
Ascierto P.A., McArthur G.A., Dreno B., Atkinson V., Liszkay G., Di Giacomo A.M., Mandala M., Demidov L., Stroyakovskiy D., Thomas L., et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): Updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17:1248-1260.
Not in our library10.1016/s1470-2045(16)30122-x
179.
Dummer R., Ascierto P.A., Gogas H.J., Arance A., Mandala M., Liszkay G., Garbe C., Schadendorf D., Krajsova I., Gutzmer R., et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19:1315-1327.
Not in our library10.1016/s1470-2045(18)30497-2
180.
Dummer R., Ascierto P.A., Gogas H.J., Arance A., Mandala M., Liszkay G., Garbe C., Schadendorf D., Krajsova I., Gutzmer R., et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19:603-615.
Not in our library10.1016/s1470-2045(18)30142-6
181.
Hamid O., Cowey C.L., Offner M., Faries M., Carvajal R.D. Efficacy, Safety, and Tolerability of Approved Combination BRAF and MEK Inhibitor Regimens for BRAF-Mutant Melanoma. Cancers. 2019;11:1642.
Not in our library10.3390/cancers11111642
182.
Hauschild A., Larkin J., Ribas A., Dreno B., Flaherty K.T., Ascierto P.A., Lewis K.D., McKenna E., Zhu Q., Mun Y., et al. Modeled Prognostic Subgroups for Survival and Treatment Outcomes in BRAF V600-Mutated Metastatic Melanoma: Pooled Analysis of 4 Randomized Clinical Trials. JAMA Oncol. 2018;4:1382-1388.
Not in our library10.1001/jamaoncol.2018.2668
183.
Long G.V., Eroglu Z., Infante J., Patel S., Daud A., Johnson D.B., Gonzalez R., Kefford R., Hamid O., Schuchter L., et al. Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. J. Clin. Oncol. 2018;36:667-673.
Not in our library10.1200/jco.2017.74.1025
184.
Long G.V., Stroyakovskiy D., Gogas H., Levchenko E., de Braud F., Larkin J., Garbe C., Jouary T., Hauschild A., Grob J.J., et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 2014;371:1877-1888.
Not in our library10.1056/nejmoa1406037
185.
Long G.V., Stroyakovskiy D., Gogas H., Levchenko E., de Braud F., Larkin J., Garbe C., Jouary T., Hauschild A., Grob J.J., et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386:444-451.
Not in our library10.1016/s0140-6736(15)60898-4
186.
Robert C., Grob J.J., Stroyakovskiy D., Karaszewska B., Hauschild A., Levchenko E., Chiarion Sileni V., Schachter J., Garbe C., Bondarenko I., et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N. Engl. J. Med. 2019;381:626-636.
Not in our library10.1056/nejmoa1904059
187.
Robert C., Karaszewska B., Schachter J., Rutkowski P., Mackiewicz A., Stroiakovski D., Lichinitser M., Dummer R., Grange F., Mortier L., et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 2015;372:30-39.
Not in our library10.1056/nejmoa1412690
188.
Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy · 2010
No notice
189.
Wongchenko M.J., McArthur G.A., Dreno B., Larkin J., Ascierto P.A., Sosman J., Andries L., Kockx M., Hurst S.D., Caro I., et al. Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib. Clin. Cancer Res. 2017;23:5238-5245.
Not in our library10.1158/1078-0432.ccr-17-0172
190.
Long G.V., Grob J.J., Nathan P., Ribas A., Robert C., Schadendorf D., Lane S.R., Mak C., Legenne P., Flaherty K.T., et al. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: A pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016;17:1743-1754.
Not in our library10.1016/s1470-2045(16)30578-2
191.
Long G.V., Hauschild A., Santinami M., Atkinson V., Mandala M., Chiarion-Sileni V., Larkin J., Nyakas M., Dutriaux C., Haydon A., et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N. Engl. J. Med. 2017;377:1813-1823.
Not in our library10.1056/nejmoa1708539
192.
Schreuer M., Jansen Y., Planken S., Chevolet I., Seremet T., Kruse V., Neyns B. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: An open-label, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol. 2017;18:464-472.
Not in our library10.1016/s1470-2045(17)30171-7
193.
Adelmann C.H., Ching G., Du L., Saporito R.C., Bansal V., Pence L.J., Liang R., Lee W., Tsai K.Y. Comparative profiles of BRAF inhibitors: The paradox index as a predictor of clinical toxicity. Oncotarget. 2016;7:30453-30460.
Not in our library10.18632/oncotarget.8351
194.
Ascierto P.A., Ferrucci P.F., Fisher R., Del Vecchio M., Atkinson V., Schmidt H., Schachter J., Queirolo P., Long G.V., Di Giacomo A.M., et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat. Med. 2019;25:941-946.
Not in our library10.1038/s41591-019-0448-9
195.
Ribas A., Lawrence D., Atkinson V., Agarwal S., Miller W.H., Carlino M.S., Fisher R., Long G.V., Hodi F.S., Tsoi J., et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat. Med. 2019;25:936-940.
Not in our library10.1038/s41591-019-0476-5
196.
Sullivan R.J., Hamid O., Gonzalez R., Infante J.R., Patel M.R., Hodi F.S., Lewis K.D., Tawbi H.A., Hernandez G., Wongchenko M.J., et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat. Med. 2019;25:929-935.
Not in our library10.1038/s41591-019-0474-7
197.
Gowrishankar K., Snoyman S., Pupo G.M., Becker T.M., Kefford R.F., Rizos H. Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. J. Investig. Dermatol. 2012;132:1850-1859.
Not in our library10.1038/jid.2012.63
198.
Roller D.G., Capaldo B., Bekiranov S., Mackey A.J., Conaway M.R., Petricoin E.F., Gioeli D., Weber M.J. Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas. Oncotarget. 2016;7:2734-2753.
Not in our library10.18632/oncotarget.6548
199.
Matheis F., Heppt M.V., Graf S.A., Duwell P., Kammerbauer C., Aigner A., Besch R., Berking C. A Bifunctional Approach of Immunostimulation and uPAR Inhibition Shows Potent Antitumor Activity in Melanoma. J. Investig. Dermatol. 2016;136:2475-2484.
Not in our library10.1016/j.jid.2016.07.026
200.
Chalbatani G.M., Dana H., Gharagouzloo E., Grijalvo S., Eritja R., Logsdon C.D., Memari F., Miri S.R., Rad M.R., Marmari V. Small interfering RNAs (siRNAs) in cancer therapy: A nano-based approach. Int. J. Nanomed. 2019;14:3111-3128.
Not in our library10.2147/ijn.s200253
201.
Sharma R., Fedorenko I., Spence P.T., Sondak V.K., Smalley K.S., Koomen J.M. Activity-Based Protein Profiling Shows Heterogeneous Signaling Adaptations to BRAF Inhibition. J. Proteome Res. 2016;15:4476-4489.
Not in our library10.1021/acs.jproteome.6b00613
202.
Cheng H., Chang Y., Zhang L., Luo J., Tu Z., Lu X., Zhang Q., Lu J., Ren X., Ding K. Identification and optimization of new dual inhibitors of B-Raf and epidermal growth factor receptor kinases for overcoming resistance against vemurafenib. J. Med. Chem. 2014;57:2692-2703.
Not in our library10.1021/jm500007h
203.
Langdon C.G., Held M.A., Platt J.T., Meeth K., Iyidogan P., Mamillapalli R., Koo A.B., Klein M., Liu Z., Bosenberg M.W., et al. The broad-spectrum receptor tyrosine kinase inhibitor dovitinib suppresses growth of BRAF-mutant melanoma cells in combination with other signaling pathway inhibitors. Pigment Cell Melanoma Res. 2015;28:417-430.
Not in our library10.1111/pcmr.12376
204.
Srivastava A., Moorthy A. Sorafenib induces synergistic effect on inhibition of vemurafenib resistant melanoma growth. Front. Biosci. Schol. Ed. 2019;11:193-202.
Not in our library10.2741/s534
205.
Bonnevaux H., Lemaitre O., Vincent L., Levit M.N., Windenberger F., Halley F., Delorme C., Lengauer C., Garcia-Echeverria C., Virone-Oddos A. Concomitant Inhibition of PI3Kbeta and BRAF or MEK in PTEN-Deficient/BRAF-Mutant Melanoma Treatment: Preclinical Assessment of SAR260301 Oral PI3Kbeta-Selective Inhibitor. Mol. Cancer Ther. 2016;15:1460-1471.
Not in our library10.1158/1535-7163.mct-15-0496
206.
Byron S.A., Loch D.C., Wellens C.L., Wortmann A., Wu J., Wang J., Nomoto K., Pollock P.M. Sensitivity to the MEK inhibitor E6201 in melanoma cells is associated with mutant BRAF and wildtype PTEN status. Mol. Cancer. 2012;11:75.
Not in our library10.1186/1476-4598-11-75
207.
Calero R., Morchon E., Martinez-Argudo I., Serrano R. Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma. Cancer Lett. 2017;406:1-11.
Not in our library10.1016/j.canlet.2017.07.021
208.
Deuker M.M., Durban V.M., Phillips W.A., McMahon M. PI3′-kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma. Cancer Discov. 2015;5:143-153.
Not in our library10.1158/2159-8290.cd-14-0856
209.
Gao M.Z., Wang H.B., Chen X.L., Cao W.T., Fu L., Li Y., Quan H.T., Xie C.Y., Lou L.G. Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma. Acta Pharmacol. Sin. 2019;40:268-278.
Not in our library10.1038/s41401-018-0020-z
210.
Greger J.G., Eastman S.D., Zhang V., Bleam M.R., Hughes A.M., Smitheman K.N., Dickerson S.H., Laquerre S.G., Liu L., Gilmer T.M. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol. Cancer Ther. 2012;11:909-920.
Not in our library10.1158/1535-7163.mct-11-0989
211.
Krepler C., Xiao M., Sproesser K., Brafford P.A., Shannan B., Beqiri M., Liu Q., Xu W., Garman B., Nathanson K.L., et al. Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin. Cancer Res. 2016;22:1592-1602.
Not in our library10.1158/1078-0432.ccr-15-1762
212.
Lassen A., Atefi M., Robert L., Wong D.J., Cerniglia M., Comin-Anduix B., Ribas A. Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma. Mol. Cancer. 2014;13:83.
Not in our library10.1186/1476-4598-13-83
213.
Ruzzolini J., Peppicelli S., Andreucci E., Bianchini F., Margheri F., Laurenzana A., Fibbi G., Pimpinelli N., Calorini L. Everolimus selectively targets vemurafenib resistant BRAFV600E melanoma cells adapted to low pH. Cancer Lett. 2017;408:43-54.
Not in our library10.1016/j.canlet.2017.08.010
214.
Sweetlove M., Wrightson E., Kolekar S., Rewcastle G.W., Baguley B.C., Shepherd P.R., Jamieson S.M. Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth. Front. Oncol. 2015;5:135.
Not in our library10.3389/fonc.2015.00135
215.
Tsukamoto S., Huang Y., Umeda D., Yamada S., Yamashita S., Kumazoe M., Kim Y., Murata M., Yamada K., Tachibana H. 67-kDa laminin receptor-dependent protein phosphatase 2A (PP2A) activation elicits melanoma-specific antitumor activity overcoming drug resistance. J. Biol. Chem. 2014;289:32671-32681.
Not in our library10.1074/jbc.m114.604983
216.
Wallin J.J., Edgar K.A., Guan J., Berry M., Prior W.W., Lee L., Lesnick J.D., Lewis C., Nonomiya J., Pang J., et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol. Cancer Ther. 2011;10:2426-2436.
Not in our library10.1158/1535-7163.mct-11-0446
217.
Galban S., Apfelbaum A.A., Espinoza C., Heist K., Haley H., Bedi K., Ljungman M., Galban C.J., Luker G.D., Dort M.V., et al. A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis. Mol. Cancer Ther. 2017;16:2340-2350.
Not in our library10.1158/1535-7163.mct-17-0207
218.
Narita Y., Okamoto K., Kawada M.I., Takase K., Minoshima Y., Kodama K., Iwata M., Miyamoto N., Sawada K. Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation in a preclinical model. Mol. Cancer Ther. 2014;13:823-832.
Not in our library10.1158/1535-7163.mct-13-0667
219.
Park S.J., Hong S.W., Moon J.H., Jin D.H., Kim J.S., Lee C.K., Kim K.P., Hong Y.S., Choi E.K., Lee J.S., et al. The MEK1/2 inhibitor AS703026 circumvents resistance to the BRAF inhibitor PLX4032 in human malignant melanoma cells. Am. J. Med. Sci. 2013;346:494-498.
Not in our library10.1097/maj.0b013e318298a185
220.
Pathria G., Garg B., Borgdorff V., Garg K., Wagner C., Superti-Furga G., Wagner S.N. Overcoming MITF-conferred drug resistance through dual AURKA/MAPK targeting in human melanoma cells. Cell Death Dis. 2016;7:e2135.
Not in our library10.1038/cddis.2015.369
221.
Phadke M.S., Sini P., Smalley K.S. The Novel ATP-Competitive MEK/Aurora Kinase Inhibitor BI-847325 Overcomes Acquired BRAF Inhibitor Resistance through Suppression of Mcl-1 and MEK Expression. Mol. Cancer Ther. 2015;14:1354-1364.
Not in our library10.1158/1535-7163.mct-14-0832
222.
Uitdehaag J.C., de Roos J.A., van Doornmalen A.M., Prinsen M.B., Spijkers-Hagelstein J.A., de Vetter J.R., de Man J., Buijsman R.C., Zaman G.J. Selective Targeting of CTNBB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs. PLoS ONE. 2015;10:e0125021.
Not in our library10.1371/journal.pone.0125021
223.
Graziani G., Artuso S., De Luca A., Muzi A., Rotili D., Scimeca M., Atzori M.G., Ceci C., Mai A., Leonetti C., et al. A new water soluble MAPK activator exerts antitumor activity in melanoma cells resistant to the BRAF inhibitor vemurafenib. Biochem. Pharmacol. 2015;95:16-27.
Not in our library10.1016/j.bcp.2015.03.004
224.
Estrela J.M., Salvador R., Marchio P., Valles S.L., Lopez-Blanch R., Rivera P., Benlloch M., Alcacer J., Perez C.L., Pellicer J.A., et al. Glucocorticoid receptor antagonism overcomes resistance to BRAF inhibition in BRAFV600E-mutated metastatic melanoma. Am. J. Cancer Res. 2019;9:2580-2598.
Not in our library
225.
Yadav V., Burke T.F., Huber L., Van Horn R.D., Zhang Y., Buchanan S.G., Chan E.M., Starling J.J., Beckmann R.P., Peng S.B. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Mol. Cancer Ther. 2014;13:2253-2263.
Not in our library10.1158/1535-7163.mct-14-0257
226.
Basken J., Stuart S.A., Kavran A.J., Lee T., Ebmeier C.C., Old W.M., Ahn N.G. Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells. Mol. Cell. Proteom. 2018;17:550-564.
Not in our library10.1074/mcp.ra117.000335
227.
Morris E.J., Jha S., Restaino C.R., Dayananth P., Zhu H., Cooper A., Carr D., Deng Y., Jin W., Black S., et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov. 2013;3:742-750.
Not in our library10.1158/2159-8290.cd-13-0070
228.
Nakamura A., Arita T., Tsuchiya S., Donelan J., Chouitar J., Carideo E., Galvin K., Okaniwa M., Ishikawa T., Yoshida S. Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma. Cancer Res. 2013;73:7043-7055.
Not in our library10.1158/0008-5472.can-13-1825
229.
Whittaker S.R., Cowley G.S., Wagner S., Luo F., Root D.E., Garraway L.A. Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors. Mol. Cancer Ther. 2015;14:2700-2711.
Not in our library10.1158/1535-7163.mct-15-0136-t
230.
Wang L., Zhu G., Zhang Q., Duan C., Zhang Y., Zhang Z., Zhou Y., Lu T., Tang W. Rational design, synthesis, and biological evaluation of Pan-Raf inhibitors to overcome resistance. Org. Biomol. Chem. 2017;15:3455-3465.
Not in our library10.1039/c7ob00518k
231.
Acquaviva J., Smith D.L., Jimenez J.P., Zhang C., Sequeira M., He S., Sang J., Bates R.C., Proia D.A. Overcoming acquired BRAF inhibitor resistance in melanoma via targeted inhibition of Hsp90 with ganetespib. Mol. Cancer Ther. 2014;13:353-363.
Not in our library10.1158/1535-7163.mct-13-0481
232.
Budina-Kolomets A., Webster M.R., Leu J.I., Jennis M., Krepler C., Guerrini A., Kossenkov A.V., Xu W., Karakousis G., Schuchter L., et al. HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors. Cancer Res. 2016;76:2720-2730.
Not in our library10.1158/0008-5472.can-15-2137
233.
Haarberg H.E., Paraiso K.H., Wood E., Rebecca V.W., Sondak V.K., Koomen J.M., Smalley K.S. Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma. Mol. Cancer Ther. 2013;12:901-912.
Not in our library10.1158/1535-7163.mct-12-1003
234.
Mielczarek-Lewandowska A., Sztiller-Sikorska M., Osrodek M., Czyz M., Hartman M.L. 17-Aminogeldanamycin selectively diminishes IRE1alpha-XBP1s pathway activity and cooperatively induces apoptosis with MEK1/2 and BRAFV600E inhibitors in melanoma cells of different genetic subtypes. Apoptosis. 2019;24:596-611.
Not in our library10.1007/s10495-019-01542-y
235.
Rebecca V.W., Wood E., Fedorenko I.V., Paraiso K.H., Haarberg H.E., Chen Y., Xiang Y., Sarnaik A., Gibney G.T., Sondak V.K., et al. Evaluating melanoma drug response and therapeutic escape with quantitative proteomics. Mol. Cell. Proteom. 2014;13:1844-1854.
Not in our library10.1074/mcp.m113.037424
236.
Smyth T., Paraiso K.H.T., Hearn K., Rodriguez-Lopez A.M., Munck J.M., Haarberg H.E., Sondak V.K., Thompson N.T., Azab M., Lyons J.F., et al. Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in melanoma models. Mol. Cancer Ther. 2014;13:2793-2804.
Not in our library10.1158/1535-7163.mct-14-0452
237.
Wu X., Marmarelis M.E., Hodi F.S. Activity of the heat shock protein 90 inhibitor ganetespib in melanoma. PLoS ONE. 2013;8:e56134.
Not in our library10.1371/journal.pone.0056134
238.
Sale M.J., Minihane E., Monks N.R., Gilley R., Richards F.M., Schifferli K.P., Andersen C.L., Davies E.J., Vicente M.A., Ozono E., et al. Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors. Nat. Commun. 2019;10:5167.
Not in our library10.1038/s41467-019-12409-w
239.
Eroglu Z., Chen Y.A., Gibney G.T., Weber J.S., Kudchadkar R.R., Khushalani N.I., Markowitz J., Brohl A.S., Tetteh L.F., Ramadan H., et al. Combined BRAF and HSP90 Inhibition in Patients with Unresectable BRAFV600E-Mutant Melanoma. Clin. Cancer Res. 2018;24:5516-5524.
Not in our library10.1158/1078-0432.ccr-18-0565
240.
Kaoud T.S., Mohassab A.M., Hassan H.A., Yan C., Van Ravenstein S.X., Abdelhamid D., Dalby K.N., Abdel-Aziz M. NO-releasing STAT3 inhibitors suppress BRAF-mutant melanoma growth. Eur. J. Med. Chem. 2020;186:111885.
Not in our library10.1016/j.ejmech.2019.111885
241.
Booth L., Roberts J.L., Sander C., Lee J., Kirkwood J.M., Poklepovic A., Dent P. The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo. Oncotarget. 2017;8:16367-16386.
Not in our library10.18632/oncotarget.14829
242.
Borst A., Haferkamp S., Grimm J., Rosch M., Zhu G., Guo S., Li C., Gao T., Meierjohann S., Schrama D., et al. BIK is involved in BRAF/MEK inhibitor induced apoptosis in melanoma cell lines. Cancer Lett. 2017;404:70-78.
Not in our library10.1016/j.canlet.2017.07.005
243.
Gallagher S.J., Gunatilake D., Beaumont K.A., Sharp D.M., Tiffen J.C., Heinemann A., Weninger W., Haass N.K., Wilmott J.S., Madore J., et al. HDAC inhibitors restore BRAF-inhibitor sensitivity by altering PI3K and survival signalling in a subset of melanoma. Int. J. Cancer. 2018;142:1926-1937.
Not in our library10.1002/ijc.31199
244.
Rowdo F.P.M., Baron A., Gallagher S.J., Hersey P., Emran A.A., Von Euw E.M., Barrio M.M., Mordoh J. Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long-term BRAF inhibition. Int. J. Oncol. 2020;56:1429-1441.
Not in our library10.3892/ijo.2020.5031
245.
Peng U., Wang Z., Pei S., Ou Y., Hu P., Liu W., Song J. ACY-1215 accelerates vemurafenib induced cell death of BRAF-mutant melanoma cells via induction of ER stress and inhibition of ERK activation. Oncol. Rep. 2017;37:1270-1276.
Not in our library10.3892/or.2016.5340
246.
Heijkants R., Willekens K., Schoonderwoerd M., Teunisse A., Nieveen M., Radaelli E., Hawinkels L., Marine J.C., Jochemsen A. Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma. Oncotarget. 2018;9:6174-6187.
Not in our library10.18632/oncotarget.23485
247.
Huijberts S., Wang L., de Oliveira R.L., Rosing H., Nuijen B., Beijnen J., Bernards R., Schellens J., Wilgenhof S. Vorinostat in patients with resistant BRAFV600E mutated advanced melanoma: A proof of concept study. Fut. Oncol. 2020;16:619-629.
Not in our library10.2217/fon-2020-0023
248.
Dorrie J., Babalija L., Hoyer S., Gerer K.F., Schuler G., Heinzerling L., Schaft N. BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy. Int. J. Mol. Sci. 2018;19:289.
Not in our library10.3390/ijms19010289
249.
Gargett T., Fraser C.K., Dotti G., Yvon E.S., Brown M.P. BRAF and MEK inhibition variably affect GD2-specific chimeric antigen receptor (CAR) T-cell function in vitro. J. Immunother. 2015;38:12-23.
Not in our library10.1097/cji.0000000000000061
250.
Tel J., Koornstra R., de Haas N., van Deutekom V., Westdorp H., Boudewijns S., van Erp N., Di Blasio S., Gerritsen W., Figdor C.G., et al. Preclinical exploration of combining plasmacytoid and myeloid dendritic cell vaccination with BRAF inhibition. J. Transl. Med. 2016;14:88.
Not in our library10.1186/s12967-016-0844-6
251.
Salton M., Kasprzak W.K., Voss T., Shapiro B.A., Poulikakos P.I., Misteli T. Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing. Nat. Commun. 2015;6:7103.
Not in our library10.1038/ncomms8103
252.
Frederick D.T., Fragomeni R.A.S., Schalck A., Ferreiro-Neira I., Hoff T., Cooper Z.A., Haq R., Panka D.J., Kwong L.N., Davies M.A., et al. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS ONE. 2014;9:e101286.
Not in our library10.1371/journal.pone.0101286
253.
Garandeau D., Noujarede J., Leclerc J., Imbert C., Garcia V., Bats M.L., Rambow F., Gilhodes J., Filleron T., Meyer N., et al. Targeting the Sphingosine 1-Phosphate Axis Exerts Potent Antitumor Activity in BRAFi-Resistant Melanomas. Mol. Cancer Ther. 2019;18:289-300.
Not in our library10.1158/1535-7163.mct-17-1141
254.
Haq R., Yokoyama S., Hawryluk E.B., Jonsson G.B., Frederick D.T., McHenry K., Porter D., Tran T.N., Love K.T., Langer R., et al. BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proc. Natl. Acad. Sci. USA. 2013;110:4321-4326.
Not in our library10.1073/pnas.1205575110
255.
Hong S.K., Starenki D., Wu P.K., Park J.I. Suppression of B-RafV600E melanoma cell survival by targeting mitochondria using triphenyl-phosphonium-conjugated nitroxide or ubiquinone. Cancer Biol. Ther. 2017;18:106-114.
Not in our library10.1080/15384047.2016.1250987
256.
Serasinghe M.N., Gelles J.D., Li K., Zhao L., Abbate F., Syku M., Mohammed J.N., Badal B., Rangel C.A., Hoehn K.L., et al. Dual suppression of inner and outer mitochondrial membrane functions augments apoptotic responses to oncogenic MAPK inhibition. Cell Death Dis. 2018;9:29.
Not in our library10.1038/s41419-017-0044-1
257.
Kosnopfel C., Sinnberg T., Sauer B., Niessner H., Schmitt A., Makino E., Forschner A., Hailfinger S., Garbe C., Schittek B. Human melanoma cells resistant to MAPK inhibitors can be effectively targeted by inhibition of the p90 ribosomal S6 kinase. Oncotarget. 2017;8:35761-35775.
Not in our library10.18632/oncotarget.16204
258.
Theodosakis N., Micevic G., Langdon C.G., Ventura A., Means R., Stern D.F., Bosenberg M.W. p90RSK Blockade Inhibits Dual BRAF and MEK Inhibitor-Resistant Melanoma by Targeting Protein Synthesis. J. Investig. Dermatol. 2017;137:2187-2196.
Not in our library10.1016/j.jid.2016.12.033
259.
Peh J., Fan T.M., Wycislo K.L., Roth H.S., Hergenrother P.J. The Combination of Vemurafenib and Procaspase-3 Activation Is Synergistic in Mutant BRAF Melanomas. Mol. Cancer Ther. 2016;15:1859-1869.
Not in our library10.1158/1535-7163.mct-16-0025
260.
Smit M.A., Maddalo G., Greig K., Raaijmakers L.M., Possik P.A., van Breukelen B., Cappadona S., Heck A.J., Altelaar A.F., Peeper D.S. ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma. Mol. Syst. Biol. 2014;10:772.
Not in our library10.15252/msb.20145450
261.
Takashima A., English B., Chen Z., Cao J., Cui R., Williams R.M., Faller D.V. Protein kinase Cdelta is a therapeutic target in malignant melanoma with NRAS mutation. ACS Chem. Biol. 2014;9:1003-1014.
Not in our library10.1021/cb400837t
262.
Wang J., Chen J., Miller D.D., Li W. Synergistic combination of novel tubulin inhibitor ABI-274 and vemurafenib overcome vemurafenib acquired resistance in BRAFV600E melanoma. Mol. Cancer Ther. 2014;13:16-26.
Not in our library10.1158/1535-7163.mct-13-0212
263.
Fattore L., Malpicci D., Marra E., Belleudi F., Noto A., De Vitis C., Pisanu M.E., Coluccia P., Camerlingo R., Roscilli G., et al. Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma. Oncotarget. 2015;6:24823-24841.
Not in our library10.18632/oncotarget.4485
264.
Kugel C.H., Hartsough E.J., Davies M.A., Setiady Y.Y., Aplin A.E. Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor. Cancer Res. 2014;74:4122-4132.
Not in our library10.1158/0008-5472.can-14-0464
265.
Pencheva N., Buss C.G., Posada J., Merghoub T., Tavazoie S.F. Broad-spectrum therapeutic suppression of metastatic melanoma through nuclear hormone receptor activation. Cell. 2014;156:986-1001.
Not in our library10.1016/j.cell.2014.01.038
266.
Asundi J., Lacap J.A., Clark S., Nannini M., Roth L., Polakis P. MAPK pathway inhibition enhances the efficacy of an anti-endothelin B receptor drug conjugate by inducing target expression in melanoma. Mol. Cancer Ther. 2014;13:1599-1610.
Not in our library10.1158/1535-7163.mct-13-0446
267.
Yu L., Favoino E., Wang Y., Ma Y., Deng X., Wang X. The CSPG4-specific monoclonal antibody enhances and prolongs the effects of the BRAF inhibitor in melanoma cells. Immunol. Res. 2011;50:294-302.
Not in our library10.1007/s12026-011-8232-z
268.
Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy · 2018
No notice
269.
Brady D.C., Crowe M.S., Greenberg D.N., Counter C.M. Copper Chelation Inhibits BRAFV600E-Driven Melanomagenesis and Counters Resistance to BRAFV600E and MEK1/2 Inhibitors. Cancer Res. 2017;77:6240-6252.
Not in our library10.1158/0008-5472.can-16-1190
270.
Babagana M., Kichina J.V., Slabodkin H., Johnson S., Maslov A., Brown L., Attwood K., Nikiforov M.A., Kandel E.S. The role of polo-like kinase 3 in the response of BRAF-mutant cells to targeted anticancer therapies. Mol. Carcinog. 2020;59:5-14.
Not in our library10.1002/mc.23123
271.
Sanchez I.M., Purwin T.J., Chervoneva I., Erkes D.A., Nguyen M.Q., Davies M.A., Nathanson K.L., Kemper K., Peeper D.S., Aplin A.E. In Vivo ERK1/2 Reporter Predictively Models Response and Resistance to Combined BRAF and MEK Inhibitors in Melanoma. Mol. Cancer Ther. 2019;18:1637-1648.
Not in our library10.1158/1535-7163.mct-18-1056
272.
Hendrix M.J., Kandela I., Mazar A.P., Seftor E.A., Seftor R.E., Margaryan N.V., Strizzi L., Murphy G.F., Long G.V., Scolyer R.A. Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells. Lab. Investig. 2017;97:176-186.
Not in our library10.1038/labinvest.2016.107
273.
Babagana M., Johnson S., Slabodkin H., Bshara W., Morrison C., Kandel E.S. P21-activated kinase 1 regulates resistance to BRAF inhibition in human cancer cells. Mol. Carcinog. 2017;56:1515-1525.
Not in our library10.1002/mc.22611
274.
Vlckova K., Reda J., Ondrusova L., Krayem M., Ghanem G., Vachtenheim J. GLI inhibitor GANT61 kills melanoma cells and acts in synergy with obatoclax. Int. J. Oncol. 2016;49:953-960.
Not in our library10.3892/ijo.2016.3596
275.
Jameson K.L., Mazur P.K., Zehnder A.M., Zhang J., Zarnegar B., Sage J., Khavari P.A. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors. Nat. Med. 2013;19:626-630.
Not in our library10.1038/nm.3165
276.
Liu W., Stachura P., Xu H.C., Ganesh N.U., Cox F., Wang R., Lang K.S., Gopalakrishnan J., Haussinger D., Homey B., et al. Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: Molecular mechanisms and clinical implications. J. Exp. Clin. Cancer Res. 2020;39:38.
Not in our library10.1186/s13046-020-1539-7
277.
Parker R., Vella L.J., Xavier D., Amirkhani A., Parker J., Cebon J., Molloy M.P. Phosphoproteomic Analysis of Cell-Based Resistance to BRAF Inhibitor Therapy in Melanoma. Front. Oncol. 2015;5:95.
Not in our library10.3389/fonc.2015.00095
278.
Krayem M., Journe F., Wiedig M., Morandini R., Najem A., Sales F., van Kempen L.C., Sibille C., Awada A., Marine J.C., et al. p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib. Eur. J. Cancer. 2016;55:98-110.
Not in our library10.1016/j.ejca.2015.12.002
279.
Ryabaya O., Prokofieva A., Akasov R., Khochenkov D., Emelyanova M., Burov S., Markvicheva E., Inshakov A., Stepanova E. Metformin increases antitumor activity of MEK inhibitor binimetinib in 2D and 3D models of human metastatic melanoma cells. Biomed. Pharmacother. 2019;109:2548-2560.
Not in our library10.1016/j.biopha.2018.11.109
280.
Theodosakis N., Langdon C.G., Micevic G., Krykbaeva I., Means R.E., Stern D.F., Bosenberg M.W. Inhibition of isoprenylation synergizes with MAPK blockade to prevent growth in treatment-resistant melanoma, colorectal, and lung cancer. Pigment Cell Melanoma Res. 2019;32:292-302.
Not in our library10.1111/pcmr.12742
281.
Brummer C., Faerber S., Bruss C., Blank C., Lacroix R., Haferkamp S., Herr W., Kreutz M., Renner K. Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma. Cancer Lett. 2019;442:453-463.
Not in our library10.1016/j.canlet.2018.11.018
282.
Barcelo C., Siso P., Maiques O., Garcia-Mulero S., Sanz-Pamplona R., Navaridas R., Megino C., Felip I., Urdanibia I., Eritja N., et al. T-Type Calcium Channels as Potential Therapeutic Targets in Vemurafenib-Resistant BRAFV600E Melanoma. J. Investig. Dermatol. 2020;140:1253-1265.
Not in our library10.1016/j.jid.2019.11.014
283.
Yuan L., Mishra R., Patel H., Abdulsalam S., Greis K.D., Kadekaro A.L., Merino E.J., Garrett J.T. Utilization of Reactive Oxygen Species Targeted Therapy to Prolong the Efficacy of BRAF Inhibitors in Melanoma. J. Cancer. 2018;9:4665-4676.
Not in our library10.7150/jca.27295
284.
Fu Y., Rathod D., Abo-Ali E.M., Dukhande V.V., Patel K. EphA2-Receptor Targeted PEGylated Nanoliposomes for the Treatment of BRAFV600E Mutated Parent- and Vemurafenib-Resistant Melanoma. Pharmaceutics. 2019;11:504.
Not in our library10.3390/pharmaceutics11100504
285.
Tham H.P., Xu K., Lim W.Q., Chen H., Zheng M., Thng T.G.S., Venkatraman S.S., Xu C., Zhao Y. Microneedle-Assisted Topical Delivery of Photodynamically Active Mesoporous Formulation for Combination Therapy of Deep-Seated Melanoma. ACS Nano. 2018;12:11936-11948.
Not in our library10.1021/acsnano.8b03007

Cited by papers we hold 3

BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers · 2023
No notice
Metastasis and MAPK Pathways · 2022
No notice
Molecular targeted therapy for anticancer treatment · 2022
No notice

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