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Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy

J. Rafael Sierra, Virna Cepero, Silvia Giordano

Molecular Cancer · 2010 · Review

Abstract

In recent years, tyrosine kinases (TKs) have been recognized as central players and regulators of cancer cell proliferation, apoptosis, and angiogenesis, and are therefore considered suitable potential targets for anti-cancer therapies. Several strategies for targeting TKs have been developed, the most successful being monoclonal antibodies and small molecule tyrosine kinase inhibitors. However, increasing evidence of acquired resistance to these drugs has been documented, and extensive preclinical studies are ongoing to try to understand the molecular mechanisms by which cancer cells are able to bypass their inhibitory activity. This review intends to present the most recently identified molecular mechanisms that mediate acquired resistance to tyrosine kinase inhibitors, identified through the use of in vitro models or the analysis of patient samples. The knowledge obtained from these studies will help to design better therapies that prevent and overcome resistance to treatment in cancer patients.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1The most common type of pharmacological anticancer treatment has been, for decades, conventional chemotherapy. This type of treatment does not discriminate between rapidly dividing normal cells and tumor cells, thus leading to severe systemic side effects, while attempting to reduce the tumor mass. In the last decade, the use of novel molecular targeted therapies has raised interest of both patients and clinicians. These treatments inhibit specific molecules that have a role in tumor growth or progression, and that are frequently altered in tumors but not in normal cells; thus, being more specific toward tumor cells, they are accompanied by reduced systemic toxicity. Nowadays, targeted therapies represent an integrative approach to cancer therapy that has already led to important clinical results.

Tyrosine Kinases

2Tyrosine kinases have been identified as signaling molecules and prototypic oncogenes, and shown to play an important role in the development of many diseases, including cancer. There is strong evidence that during tumor progression, the hyperactivation of tyrosine kinases leads to the continuous activation of downstream signaling cascades that block cellular apoptosis, promote cellular proliferation, and increase the nutrient/waste interchange by enhancing angiogenesis.

3Receptor Tyrosine Kinases (RTKs) are single pass transmembrane proteins that account for almost two thirds of the genes coding for tyrosine kinases. RTKs possess a common functional kinase domain that is able to translate extracellular signals into active intracellular cues. Under physiological conditions, these receptors are activated only upon ligand binding. Activation of the kinase is achieved by ligand-binding to the extracellular domain, which induces homo/hetero-dimerization of the receptors. Activated receptors phosphorylate tyrosine residues outside their catalytic domain via cross-phosphorylation. This phosphorylation stabilizes the receptor conformation in an active state and creates phosphotyrosine docking sites for proteins which transduce signals within the cell.

4In cancer, this mechanism of ligand-dependent activation can be bypassed by (i) overexpression of the RTK, which increases the dynamics of receptor homo/heterodimerization in the absence of the ligand; (ii) by activating mutations, which stabilize the receptor active conformation; or (iii) by autocrine stimulation. These mechanisms lead to cell autonomous activation of RTKs that drive proliferative and anti-apoptotic signals, contributing to transformation.

5Non-Receptor Tyrosine Kinases (NRTKs), the second class of TKs, account for the remaining third of the approximately 90 known TKs and are critical signal transducers. Some examples include the well-known and well-characterized NRTKs Src, JAK, c-Abl and FAK. Interestingly, NRTKs were the first tyrosine kinases discovered. Their involvement in cancer can occur through various mechanisms such as overexpression, mutation, and translocation; and therefore, many compounds have been developed attempting to inhibit their activity.

6Treatments with tyrosine kinase inhibitors (TKIs), in some cases, have given promising results. However, most tumors treated with TKIs became resistant to treatment in a short time. In other words, just as bacteria develop resistance to antibiotics, neoplastic cells can acquire new traits that render them more aggressive and able to survive in the presence of molecular inhibitors.

7Clinical experience has shown that only a percentage of patients respond to targeted therapies, even if their tumor expresses the altered target. This primary resistance to treatment is often due to constitutive activation of downstream signal transducers. Recently, many reports have evidenced that patients carrying activating mutations in effectors downstream of the targeted molecule account for the majority of the non-responsive patients.

8Given that many patients are starting to benefit from tyrosine kinase inhibitors, including monoclonal antibodies and small molecule inhibitors, clinicians and basic researchers are now trying to unveil and understand the mechanisms through which neoplastic cells loose their ability to respond to these drugs (also known as secondary resistance or acquired resistance). Luckily, it appears that the majority of the resistance models developed in vitro are predictive of what is observed in vivo and can thus help researchers in identifying and studying this crucial clinical problem.

9This review will attempt to provide an updated compendium of cellular modifications that contribute to acquired resistance to TKIs, highlighting the importance of preclinical studies of these drugs.

Targeting Tyrosine Kinases

10Many research groups, including ours, have shown that the inhibition of RTKs in neoplastic cells - by administration of monoclonal antibodies, interfering RNAs, and/or small kinase inhibitors (TKIs) - impairs cell proliferation and survival, inducing arrest of cell growth and apoptosis. Based on these findings, many pharmaceutical companies have invested in designing or identifying new methods of inhibiting tyrosine kinases.

Small molecule tyrosine kinase inhibitors

11Pharmaceutical companies have focused their research on the development of small TKIs, some of which have received the approval of governmental drug administration agencies. Additional file 1 lists some TKIs currently approved or undergoing clinical trials. TKIs are small molecules that inhibit the enzymatic activity of the target protein. Most of these molecules can be categorized into four groups: (i) ATP-competitive inhibitors, which bind predominantly to the ATP-binding site of the kinase when this site is in the active conformation; (ii) inhibitors that recognize and bind to the non-active conformation of the ATP-binding site of the kinase, thus making activation energetically unfavorable; (iii) allosteric inhibitors, that bind outside of the ATP-binding site, modifying the tridimensional structure of the receptor and disrupting the interaction between the ATP and the kinase pocket; and (iv) covalent inhibitors, that bind irreversibly by covalently bonding to the ATP-binding site of the target kinase (reviewed in).

12While monoclonal antibody (mAb) therapy is particularly suited for extracellular (membrane-bound or secreted) targets, small-molecule kinase inhibitors are effective against both membrane-bound and intracellular targets. While both therapies have advantages and disadvantages when compared to each other, the major differences between monoclonal antibodies and small TKIs are the modality of administration, the bioavailability and half-life, and the mechanisms of resistance to the therapeutic agents. (See comparison table 1).

Monoclonal Antibodies

13Immunotherapy is based on the production of humanized monoclonal antibodies (mAbs) that bind with high specificity to secreted proteins or to the extracellular domain of membrane-bound proteins. The use of mAbs relies on the principle that most of the targeted molecules are expressed at higher levels on neoplastic cells, when compared to normal cells, where they play an important role in sustaining cancer progression. So far, there are several mechanisms described by which they exert their therapeutic effects; among them are: binding to the ligand or to the receptor, thus preventing ligand-receptor interaction; disrupting receptor internalization, promoting receptor internalization, shedding of the extracellular portion of the receptor, preventing receptor dimerization and activation, and induction of apoptosis. However, it is believed that each mAb acts through more than one mechanism. In addition, evidence has shown that activation of the immune response against the targeted tumor cells, upon recognition of the bound antibody, can also account for their biological activity. Table 2 lists monoclonal antibodies directed again tyrosine kinases currently used in preclinical and clinical studies.

14Monoclonal antibodies have been widely used in the clinic and have shown promising results, but unfortunately many patients relapse due to development of mechanisms of resistance. Information obtained from cellular models and relapsed patients has provided insights on how cells adapt to the treatment, by reducing the expression or modifying the structure of the target protein or activating alternative survival pathways.

Genetic modifications

15Clinical and in vitro evidence have shown that cells treated with TKIs tend to acquire genetic modifications to overcome the inhibitory effects of these agents. Common mechanisms of resistance include, but are not limited to: point mutations, deletions and amplifications of genomic areas. A schematic summary of the main molecular mechanisms of acquired resistance to small molecules is represented in Figure 1.

Mutations

16Mutations are common and occur frequently in rapidly dividing cancer cells. Point mutations are the most common mechanism of resistance to TKIs. The most frequent types of mutations are those that decrease the affinity of the drug for the target kinase domain, while maintaining its catalytic activity. Other mutations alter the amino acids surrounding the binding site of the drug and decrease the availability of the target region towards the inhibitor, without interfering with ATP binding. Finally, some mutations increase the affinity of the kinase for ATP, decreasing the effectiveness of the ATP-competitive inhibitors.

17The strongest evidence comes from imatinib, a small tyrosine kinase inhibitor that was found to bind with high affinity to c-Abl kinase. Imatinib is used to treat Chronic Myeloid Leukemia (CML) patients who express a constitutively active c-Abl tyrosine kinase, the BCR-ABL fusion protein. Imatinib abrogates the oncogenic function of BCR-ABL by binding the protein in its inactive state, thus preventing its autophosphorylation and, therefore, blocking the activation of downstream signal transducers. The use of imatinib has improved the life expectancy of CML patients, but major concerns have been raised for this and other TKIs by the rapid development of mechanisms of resistance. The majority of the CML patients in advanced stage (66%) and some in the chronic phase (5%) relapse after imatinib treatment, developing c-Abl dependent and independent mechanisms of resistance. Approximately 30-50% of the relapsed patients acquire point mutations (around 90 distinct point mutations identified so far) that change the conformation of the c-Abl kinase, reducing or abrogating the ability of the compound to bind the c-Abl kinase domain. This molecular mechanism of resistance has been supported also by structural studies which have shown that imatinib cannot efficiently interact with the ATP binding pocket in the mutated forms of BCR-ABL. When reports started to show that mutations in the kinase domain of c-Abl were present in relapsed patients, and experimental work showed that the mutant kinase was no longer inhibited by imatinib, second generation inhibitors, such as dasatinib, nilotinib, sunitinib, and bosutinib were designed. These new molecules are able to recognize and bind BCR-ABL in different conformations, and are thus suitable for imatinib-relapsed patients. Dasatinib and nilotinib are able to interact with most of the mutated imatinib-resistant c-Abl forms, with the exception of the T315I mutant that changes the kinase and modifies several contact points between the drug and the kinase, while preserving the kinase activity. The only inhibitor so far that has been proven to inhibit this mutant is the multikinase inhibitor KW-2449. However, CML patients who used these second generation inhibitors developed resistance by acquiring new mutations in the kinase domain.

18Why do patients develop these mutations during treatment? There are reports that support the idea that the appearance of mutations in tumors after treatment with a specific TKI is the result of a process of selection of a pre-existing cell population. This theory implies that a small population of the tumor bulk a priori contains the mutation, which confers a primary resistance to these cells, therefore giving them a selective advantage. The bulk tumor mass is thus killed by the drug, allowing cells resistant to the TKI to grow. This theory is supported by the fact that some of these "resistance related mutations" can be found in a small percentage of tumor cells in patients that have not yet undergone targeted therapy. On the other hand, other researchers believe that the high dependence of a cell on a specific oncogenic survival pathway forces genomic instability, allowing the induction of mutations that confer resistance to the inhibitor. This genomic instability can induce mutations either in the drug target or in other signal transducers that activate alternative pathways able to sustain cell viability. This theory has been supported by groups who have induced resistance to TKIs in imatinib-sensible CML cell lines cloned by limiting dilution; they have found the appearance of BCR-ABL gene amplification and of point mutations in the kinase domain that were not present in the original cells.

19Further studies revealed that imatinib also binds with high affinity to the cKIT and PDGFR kinases, frequently activated in Gastrointestinal Stromal Tumors (GIST). GISTs are the first solid tumors in which a tyrosine kinase inhibitor was used as standard care. As these tumors often display mutations in the tyrosine kinase receptors cKIT and PDGFR, imatinib was used to inhibit their activity. Like CML patients, 50-70% of GIST patients treated with imatinib develop secondary mutations within the cKIT gene, conferring a reduced drug binding affinity but still retaining the kinase activity. To suppress the kinase activity of the resistant cKIT mutants, sunitinib was developed. As previously observed in patients treated with other inhibitors of second generation, imatinib-resistant GIST patients treated with sunitinib developed new mutations that made them again resistant to the new drug.

20Gefitinib and erlotinib are small molecule TKIs targeting the Epidermal Growth Factor Receptor (EGFR) that have been used to treat tumors where this RTK is known to be altered. In particular, they have been used to treat non-small cell lung carcinomas (NSCLC) where EGFR is frequently overexpressed or activated due to point mutations. According to a compendium of studies that include 1170 patients, more than 70% of NSCLCs with EGFR mutations respond to EGFR-TKIs, whereas only 10% of tumors without EGFR mutations do so. Unfortunately, upon treatment of these patients with gefitinib and erlotinib, two major mechanisms of resistance have been observed. The first is the appearance of a "resistance" point mutation in the kinase domain (T790M), observed in 50% of the gefitinib-resistant patients. This mutation increases the affinity for ATP and weakens the affinity for ATP-competitive inhibitors. On the other hand, the second mechanism is the activation of an alternative oncogene able to compensate for the inhibited signaling pathways.

21Interestingly, in vitro models of acquired resistance to gefitinib, obtained by exposing gefitinib-sensitive cells to increasing concentrations of the drug, led to the appearance of the same mutations identified in patients. This has allowed scientists to study the mechanisms through which these mutations modulate sensitivity to the drug. Lapatinib is another EGFR inhibitor, recently approved for treatment of breast cancer. This inhibitor has been designed to block receptor signaling by binding to the ATP-binding pocket of EGFR and ERBB2 kinase domains, thus preventing phosphorylation and subsequent downstream signaling from these two receptors. Using a randomly mutagenized ERBB2 library in vitro, Trowe et al. were able to identify 12 mutations in the kinase domain of ERBB2 that could confer resistance to the inhibitor. Moreover, this same work showed that a new generation inhibitor, EXEL-7647, is still active on all the mutants.

22Similarly, activating mutations in the FLT3 RTK occur frequently in Acute Myelogenous Leukemia (AML). When AML patients were treated with PKC412, a staurosporin derivative able to inhibit FLT3's kinase activity, patients rapidly developed point mutations in the kinase domain of FLT3 that rendered the kinase less accessible to the inhibitor. These same mutations had been previously foreseen by a computational predictive analysis and confirmed by in vitro data when Cools et al. identified possible mutations in residues conferring a high level of resistance to small molecules. Recently, another cellular model has predicted new point mutations that confer resistance to FLT3 inhibitors such as SU5614, PKC412, and sorafenib. As the different FLT3 kinase inhibitors generated distinct, non-overlapping mutational profiles, the authors propose that a combination of FLT3 inhibitors might be useful to prevent the appearance of FLT3 resistance mutations.

23As previously mentioned, another clinically approved TKI currently in use is sorafenib. This small molecular multikinase inhibitor, primarily targets BRAF and can inhibit several other TKs such as PDGFR, VEGFR 1-2, FLT3, and cKIT. This multi-target drug possesses anti-tumoral and anti-angiogenic properties due to its broad blocking activity. The use of sorafenib, just as with other small molecule inhibitors, has caused so far a variety of mutations in PDGFR, FLT3, and BRAF that confer resistance to the treatment.

Gene Amplification

24Gene amplification is a major mechanism of oncogenic activation. Preclinical and clinical data have shown that the presence of either activating mutations in the kinase domain or gene amplification correlate with the best response to TKI. Unfortunately, the selective pressure of the drug can drive further amplification of the target gene, thus leading to additional overexpression of the encoded protein. This idea originates from in vitro studies that have shown that highly amplified oncogenes are located in extrachromosomal acentromeric double minutes, and such cells undergoing "oncogenic stress" may undergo further gains due to advantageous unsymmetrical nuclear division. These gains alter the stoichiometry of the drug-target interaction in favor of the target and result in its inefficient inhibition. This event has been observed in CML relapsed patients treated with imatinib, who displayed an increase in the BCR-ABL gene copy number. In these patients, an increase in drug dosage is usually sufficient to restore responsiveness to the treatment. This same mechanism of resistance had been observed in an in vitro model where a CML cell line was treated for a long period of time with imatinib. Likewise, the emergence of amplification of the target gene as a mechanism of resistance has been observed in two other cases where resistance cells amplified EGFR or FTL3 in response to inhibitors.

25Another way through which gene amplification can mediate resistance to treatment is via amplification of genes that encode for critical transducers driving signaling pathways that can compensate for the signals lost due to target inhibition. A notable example is the amplification of the MET gene, encoding for the receptor tyrosine kinase for hepatocyte growth factor, in a percentage of gefitinib-relapsed patients affected by NSCLC. These results perfectly correlated with those obtained in in vitro studies after treating sensitive NSCLC cell lines with progressively increasing doses of gefitinib or other EGFR inhibitors. In these experiments, MET overexpression led to its constitutive activation by a ligand-independent mechanism, which later resulted in advantageous interactions with other EGFR family members, mainly ERBB3, and activation of downstream signals. Inhibition of MET, in this context, restored sensitivity to EGFR inhibitors.

Genomic Deletions

26Other genomic alterations frequently observed upon TKI treatment are deletions. Khorashad and collaborators performed a genome-wide study comparing DNA samples from CML patients prior to imatinib treatment and after relapse. CGH analyses for all patients revealed that 28% of the copy number alterations were genomic deletions. Among the genes that were most frequently altered were those involved in the control of the MAPK signaling pathway.

27Among the genes that are frequently deleted in human cancers are those encoding microRNAs (miRNAs). MiRNAs have emerged as a novel class of regulatory genes involved in human cancer. Lacking the ability to encode a protein, these single-stranded miRNAs bind to imperfectly complementary sequences of encoding mRNAs, causing these mRNA sequences to be silenced or degraded, resulting in reduced levels of the protein encoded by the mRNA. Many reports have highlighted the relevance of these non-coding RNA's in human cancer, where they are frequently altered, more often as consequence of their deletion. Various groups have reported cases where the deletion of miRNA regions has led to overexpression of the targeted RTKs, due to lack of down-regulation. In this context, Seike and collaborators recently correlated high EGFR activation with high expression of mir-21 both in NSCLC patient samples and cell lines. They report that inhibition of EGFR by the small molecule AG1478 reduced the levels of this miRNA, concluding that the activation status of the receptor modulates the expression of this anti-apoptotic miRNA. As it considered a growing field of interest, various groups have reported that miRNA expression can mediate resistance to different types of chemotherapy (reviewed in), and it is very likely that quite soon miRNAs will also be found to play a role in mediating resistance to TKIs.

Modifications of protein expression

28Cells seem to possess a broad repertoire of adaptive reactions that enable them to survive in many adverse conditions. One of the adaptive traits is the overexpression or the repression of genes that sustain cell viability. Mahon et al. recently demonstrated that nilotinib-resistant CML cell lines were able to upregulate the expression of BCR-ABL, thus overcoming the inhibitory threshold of nilotinib. Although this and other similar works lack evidence that the overexpression of the target protein is not due to gene amplification (also known mechanism of resistance to BCR-ABL TKI), this can be considered as a new mechanism of resistance.

29This last response does not involve genetic alterations, but simply changes in gene expression, due to microenvironmental stress or to epigenetic modifications. It is known that the use of TKIs can lead to reduced blood flow, which in turn increases the incidence of hypoxic areas. Moreover, hypoxia is known to upregulate HIF-1a, a protein that can promote the expression of many genes including the RTK MET, which is capable of sustaining the MAPK and PI3K survival pathways.

30Likewise, epigenetic changes can also contribute to TKI resistance. For example, Noro et al. reported an in vitro model where lung cancer cells resistant to gefitinib displayed hypermethylation of the PTEN gene promoter; exogenous re-expression of this enzyme restores senstivity to the EGFR inhibitor.

Activation of alternative pathways

31Some cells can replace the lack of signal due to target inhibition by activating alternative pathways. The EGFR family of receptors has been shown to develop mechanisms of resistance by modifying the expression of several downstream effectors. For example, Pandya and collaborators developed a cellular model where colorectal carcinoma HCT116 cells, which depend on ERBB2 activity, lose their sensitivity to lapatinib. The major mechanism of resistance observed was the increased expression of MCL-1, and the decreased expression and activity of BAX and BAK, altogether leading to decreased apoptotic responses. Another proposed mechanism of resistance was reported by Xia et al. who showed that lapatinib-resistant breast cancer cells and lapatinib-treated patients displayed an increased level of the Estrogen Receptor and the transcription factor FoxoA3. Another example was recently reported by Turke et al. where EGFR-dependent cells stimulated with MET's ligand, HGF, were resistant both in vivo and in vitro, and such effect could be blocked by the use of MET inhibitors. In a similar manner, McDermott et al. reported that MET-dependent NSCLC cells activate EGFR as a mechanism of resistance to PF2341066 (an irreversible MET kinase inhibitor) using an increasing dose resistant cellular model.

32Another mechanism of resistance that was reported in NSCLC patients and in cell lines resistant to gefitinib treatment is the cross-talk between the EGFR/ERBB2 receptors and the IGF-1R receptor. This mechanism of resistance relies on the fact that cells utilize IGF-1R to activate survival pathways that are able to promote growth. One report shows that a prostate cancer cell line which became resistant to gefitinib displayed an increase of IGFII mRNA and IGF-1R protein phosphorylation. Moreover, it was also published that a gefitinib-resistant lung squamous carcinoma cell line lost the production of IGFBP3-4 when compared to the parental cells; re-expression of these proteins restored the sensitivity to gefitinib's cytostatic effect.

33The activation of an alternative kinase is known to overcome the inhibitory effects of small molecules. For example, GIST cells resistant to imatinib exhibited increased levels of the AXL receptor, that could in turn activate the AKT pathway and thus overcome c-KIT inhibition. Two different groups have recently shown that in a cellular model of CML, TKI-resistant cells display activation of the Src kinase LYN; inhibition of this kinase by the use of dasatinib restores sensitivity to imatinib or nilotinib.

34In a similar manner, the human myelomonoblastic cell line MV4-11, generated to be resistant to PKC412, displayed an up-regulation of anti-apoptotic genes and down-regulation of proapoptotic signals as well as genes that are involved in normal and malignant hematopoiesis.

35Recently, Huang et al. reported that tumor xenografts resistant to sunitinib secreted higher amounts of IL-8 (proangiogenic factor known to be induced by several key regulators of cell survival and hypoxia) which at the same time positively correlated with a higher tumor vessel density.

36Another commonly observed mechanism of resistance to TKI is the overexpression of survivin a member of the inhibitor of apoptosis family, encoded by the BIRC5 gene. This cancer therapy candidate gene is overexpressed in a large variety of human tumors and its expression is absent in terminally differentiated. Survivin is known to inhibit caspase activation, and therefore, leading to negatively regulate apoptosis or programmed cell death, and it has been correlated with both accelerated relapse and chemotherapy resistance. Xia et al. have demonstrated that overexpression of surviving can mediate resistance to lapatinib; such finding was observed by generating lapatinib-resistant breast cancer cells in vitro and correlating clinical observations.

Mechanisms of Resistance related to drug influx/efflux

37There are many mechanisms implicated in the decrease of the effective intracellular concentration of a drug, leading to lack of response to treatment. Among the most important resistance mechanisms are: increased drug influx/efflux and drug plasma sequestration. Other factors that can contribute to decreased drug delivery to tumors include irregular blood flow, defects in the structure and permeability of tumor vasculature and drug diffusion in the interstitium.

38The occurrence of multidrug resistance (MDR) is a very frequent cause of failure of chemotherapeutic treatment in cancer patients. MDR proteins are transmembrane pumps responsible for the active efflux of a broad range of structurally unrelated molecules. This efflux can occur despite considerable concentration gradients at the expense of ATP depletion, resulting in decreased intracellular drug accumulation. It is conceivable that TKIs may inhibit the function of ATP-binding cassette (ABC) transporters by recognizing their ATP-binding sites. In fact, some of these small molecules such as cediranib, lapatinib, and sunitinib have proven to be effective in reversing MDR associated to chemotherapeutics, by directly inhibiting the transport function of some ABC members. This ability renders them useful options for cancer combinational therapy. The initial success of molecularly targeted therapies raised hope that newly developed agents would evade the general mechanisms of resistance that have reduced the efficacy of traditional anticancer drugs. However, ABC transporters related to MDR have emerged as key factors that regulate the intracellular concentrations of many small-molecule inhibitors. Drug transporters may be overexpressed in cancer cells, reducing intracellular drug concentrations, and may allow the evolution of point mutations that confer stronger drug resistance.

39Mahone and collaborators demonstrated that imatinib-resistant cell lines overexpressed the P-glycoprotein (P-gp) efflux pump. This concept was reinforced when imatinib sensitivity was restored when P-gp pumps were blocked by different inhibitors, or silenced using RNAi. All this data indicates that P-gp is a likely candidate contributing to imatinib resistance, and some in vitro data suggests that this may also be true for resistance to nilotinib. Dasatinib and sunitinib have been shown to be a substrate of both efflux proteins, ABCB1 and ABCG2. ABCG2 has also been shown to bind gefitinib with high affinity, causing an active extrusion of the inhibitor and thus preventing its biological activity.

40In addition, multiple reports have provided evidence that deregulation of the organic cation transporter hOCT1 can impede the influx of imatinib. Using hOCT inhibitors on different imatinib-sensitive CML cells caused a reduced uptake of imatinib. This finding was further supported by clinical data showing that patients who display a minimal response to imatinib also express a significantly lower amount of hOCT. Therefore, intracellular drug levels depend in part on the differential expression of influx and efflux transporters, which are determinants of TKI resistance.

41Another method by which tumors bypass the inhibitory effects of TKI is by the sequestration of such drugs by plasma proteins, such as the plasma protein-1 acid glycoprotein (AGP). It has been shown in vitro and in vivo that AGP binds to imatinib, and this binding decreases imatinib's ability to inhibit c-ABL in a dose-dependent manner, findings supported by clinical data.

Mechanisms of resistance to monoclonal antibodies

42Although monoclonal antibodies have given very good results in the clinic, the emergence of resistance is also frequently observed upon treatment with these agents. Several mechanisms of resistance have been observed in preclinical and clinical studies, mostly with antibodies that have already undergone FDA approval. In the case of monotherapy, preexistence of mutations in the MAPK or PI3K signaling pathways is one of the major causes of primary or intrinsic resistance. In 2009, the American Society of Clinical Oncology suggested that metastatic colorectal cancer (CRC) patients who displayed an alteration in codon 12 or 13 of KRAS should not be considered for monoclonal therapy. This decision was based on multiple studies that have shown that activating mutations in KRAS, PIK3CA, BRAF and loss of expression of PTEN correlated negatively with cetuximab or panitumumab response (reviewed in).

43Patients undergoing monotherapy are also prone to develop secondary or acquired resistance to such treatment. So far, no mAb therapy has given rise to any point mutation in the target receptor or rearrangements in genomic regions. The mechanisms described up to now typically involve variations in protein expression. At least five modifications of this type have been shown to contribute to resistance to mAbs:

44(i) Overexpression and aberrant phosphorylation of alternative RTKs attempting to overcome the inhibition of the targeted protein. In 2008, Wheeler et al. generated NSCLC and HNSCC cetuximab-resistant cell lines, such resistance was mediated by the increased expression of ERBB2, ERBB3, and MET which can interact with other EGFR family members contributing to their activation. In a similar way, Lu et al. and Shattuck et al. have shown that cells can overcome trastuzumab inhibition by the activation of IGF-1R and MET, respectively.

45(ii) The second known protein modification is expression of receptor variants. Sok and collaborators demonstrated that a mutant variant of EGFR (EGFRvIII), which lacks the ligand binding domain, is expressed in more than 42% of HNSCC. In their experiments, overexpression of EGFRvIII in HNSCC cells decreased in the inhibitory response to cetuximab.

46(iii) The third protein modification involves the targeted protein; in this type of resistance, cells display an increased expression of the target receptor. Reports have shown that NSCLC cell lines resistant to cetuximab display an increase in EGFR protein levels due to a defective deregulation in the degradation pathways.

47(iv) Activation of alternative pathways is another mechanism of resistance. It has been observed that cells resistant to either cetuximab or trastuzumab can develop a dependency on new signaling pathways either by triggering the same biological effects by interaction with other EGFR family members, or by association with other kinases such as Src. Valabrega et al. reported that TGFα (an EGFR ligand) overexpression can contribute to resistance. It is interesting to note that the overexpression of ligands is not a rare event, since patients and cell lines resistant to bevacizumab (a VEGF blocking antibody) cause tumor cells to secrete additional angiogenic factors (FGF, PGF, members of the notch ligand/receptor family) to compensate for the lack of VEGF signaling.

48Lastly, (v) the lack of interaction between the target and the mAb due to steric hindrance caused by the formation of complexes with other cell surface proteins, such as in the case of resistance to trastuzumab. It is known that the expression of MUC4, a membrane-associated mucin that contributes to the masking of membrane proteins, decreases the amount of trastuzumab that can bind to ERBB2 When MUC4 was silenced in trastuzumab resistant cells, cells were once again sensitive to the mAb.

Conclusions

49New clinical and laboratory studies have suggested that multi-targeting approaches against neoplastic cells could help to increase patient survival and, possibly, reduce the emergence of cells resistant to single-target inhibitors. This increased activity will have to be balanced by the expected increased toxicity due to the association of the drugs. Moreover, combination mAbs and multi-target small molecules could be also a very promising therapeutic approach.

50Accumulating experimental and clinical evidences have supported the idea that targeted therapy should be reassessed. In particular, we should keep in mind that tumors are the result of multiple genetic lesions. Clinicians and researchers should not underestimate the capacity of tumors to easily adapt to new stress conditions, therefore inducing or selecting those cells that can better survive in the presence of an inhibitor.

Abbreviations

51CML: Chronic myelogenous leukemia; CRC: colorectal cancer; EGFR: epidermal growth factor receptor; GIST: gastrointestinal stromal tumors; HGF: hepatocyte growth factor; HNSCC: head and neck squamous cell carcinoma; mAb: monoclonal antibody; MET: hepatocyte growth factor receptor; NSCLC: non-small cell lung carcinoma; NRTK(s): non-receptor tyrosine kinase(s); RTK(s): receptor tyrosine kinase(s); TGFα: transforming growth factor alpha; TKI(s): tyrosine kinase inhibitor(s).

Competing interests

52The authors declare that they have no competing interests.

Authors' contributions

53JRS drafted and wrote the manuscript. VC helped writing the manuscript. SG corrected and finalized the manuscript. All authors read and approved the final manuscript.

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Not in our library10.1634/theoncologist.8-6-531
18.
Engelman JA Settleman J Acquired resistance to tyrosine kinase inhibitors during cancer therapyCurr Opin Genet Dev2008 187379
Not in our library10.1016/j.gde.2008.01.004
19.
Sartore-Bianchi A Martini M Molinari F Veronese S Nichelatti M Artale S Di Nicolantonio F Saletti P De Dosso S Mazzucchelli L PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodiesCancer Res2009 6918511857
Not in our library10.1158/0008-5472.can-08-2466
20.
de Reynies A Boige V Milano G Faivre J Laurent-Puig P KRAS mutation signature in colorectal tumors significantly overlaps with the cetuximab response signatureJ Clin Oncol2008 2622282230author reply 2230-2221.
Not in our library10.1200/jco.2007.15.9186
21.
Bonomi PD Buckingham L Coon J Selecting patients for treatment with epidermal growth factor tyrosine kinase inhibitorsClin Cancer Res2007 13s46064612
Not in our library10.1158/1078-0432.ccr-07-0332
22.
KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib · 2005
No notice
23.
Zhu CQ da Cunha Santos G Ding K Sakurada A Cutz JC Liu N Zhang T Marrano P Whitehead M Squire JA Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21J Clin Oncol2008 2642684275
Not in our library10.1200/jco.2007.14.8924
24.
Corso S Migliore C Ghiso E De Rosa G Comoglio PM Giordano S Silencing the MET oncogene leads to regression of experimental tumors and metastasesOncogene2008 27684693
Not in our library10.1038/sj.onc.1210697
25.
Normanno N Bianco C Damiano V de Angelis E Selvam MP Grassi M Magliulo G Tortora G Bianco AR Mendelsohn J Growth inhibition of human colon carcinoma cells by combinations of anti-epidermal growth factor-related growth factor antisense oligonucleotidesClin Cancer Res1996 2601609
Not in our library
26.
McDermott U Sharma SV Dowell L Greninger P Montagut C Lamb J Archibald H Raudales R Tam A Lee D Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profilingProc Natl Acad Sci USA2007 1041993619941
Not in our library10.1073/pnas.0707498104
27.
Vigna E Pacchiana G Mazzone M Chiriaco C Fontani L Basilico C Pennacchietti S Comoglio PM "Active" cancer immunotherapy by anti-Met antibody gene transferCancer Res2008 6891769183
Not in our library10.1158/0008-5472.can-08-1688
28.
Montagut C Settleman J Targeting the RAF-MEK-ERK pathway in cancer therapyCancer Lett2009 283125134
Not in our library10.1016/j.canlet.2009.01.022
29.
Zhang J Yang PL Gray NS Targeting cancer with small molecule kinase inhibitorsNat Rev Cancer2009 92839
Not in our library10.1038/nrc2559
30.
Shih YC Halpern MT Economic evaluations of medical care interventions for cancer patients: how, why, and what does it mean?CA Cancer J Clin2008 58231244
Not in our library10.3322/ca.2008.0008
31.
Imai K Takaoka A Comparing antibody and small-molecule therapies for cancerNat Rev Cancer2006 6714727
Not in our library10.1038/nrc1913
32.
Slamon DJ The FUTURE of ErbB-1 and ErbB-2 pathway inhibition in breast cancer: targeting multiple receptorsOncologist2004 9Suppl 313
Not in our library10.1634/theoncologist.9-suppl_3-1
33.
Song JY Lee SW Hong JP Chang SE Choe H Choi J Epidermal growth factor competes with EGF receptor inhibitors to induce cell death in EGFR-overexpressing tumor cellsCancer Lett2009 283135142
Not in our library10.1016/j.canlet.2009.03.034
34.
Guin S Yao HP Wang MH RON Receptor Tyrosine Kinase as a Target for Delivery of Chemodrugs by Antibody Directed Pathway for Cancer Cell CytotoxicityMol Pharm2010 7238697
Not in our library10.1021/mp900168v
35.
Wheeler DL Huang S Kruser TJ Nechrebecki MM Armstrong EA Benavente S Gondi V Hsu KT Harari PM Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family membersOncogene2008 2739443956
Not in our library10.1038/onc.2008.19
36.
Petrelli A Circosta P Granziero L Mazzone M Pisacane A Fenoglio S Comoglio PM Giordano S Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activityProc Natl Acad Sci USA2006 10350905095
Not in our library10.1073/pnas.0508156103
37.
Molina MA Codony-Servat J Albanell J Rojo F Arribas J Baselga J Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cellsCancer Res2001 6147444749
Not in our library
38.
Hudziak RM Lewis GD Winget M Fendly BM Shepard HM Ullrich A p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factorMol Cell Biol1989 911651172
Not in our library10.1128/mcb.9.3.1165-1172.1989
39.
Meira DD Nobrega I de Almeida VH Mororo JS Cardoso AM Silva RL Albano RM Ferreira CG Different antiproliferative effects of matuzumab and cetuximab in A431 cells are associated with persistent activity of the MAPK pathwayEur J Cancer2009 4512651273
Not in our library10.1016/j.ejca.2008.12.012
40.
Petrelli A Valabrega G Multitarget drugs: the present and the future of cancer therapyExpert Opin Pharmacother2009 10589600
Not in our library10.1517/14656560902781907
41.
Kurai J Chikumi H Hashimoto K Yamaguchi K Yamasaki A Sako T Touge H Makino H Takata M Miyata M Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell linesClin Cancer Res2007 1315521561
Not in our library10.1158/1078-0432.ccr-06-1726
42.
Nielsen DL Andersson M Kamby C HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitorsCancer Treat Rev2009 35121136
Not in our library10.1016/j.ctrv.2008.09.003
43.
Tanaka R Kimura S Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generationExpert Rev Anticancer Ther2008 813871398
Not in our library10.1586/14737140.8.9.1387
44.
Hochhaus A La Rosee P Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistanceLeukemia2004 1813211331
Not in our library10.1038/sj.leu.2403426
45.
Melo JV Chuah C Resistance to imatinib mesylate in chronic myeloid leukaemiaCancer Lett2007 249121132
Not in our library10.1016/j.canlet.2006.07.010
46.
Litzow MR Imatinib resistance: obstacles and opportunitiesArch Pathol Lab Med2006 130669679
Not in our library10.5858/2006-130-669-iroao
47.
Branford S Chronic myeloid leukemia: molecular monitoring in clinical practiceHematology Am Soc Hematol Educ Program2007 2007376383
Not in our library10.1182/asheducation-2007.1.376
48.
O'Hare T Walters DK Stoffregen EP Jia T Manley PW Mestan J Cowan-Jacob SW Lee FY Heinrich MC Deininger MW Druker BJ In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutantsCancer Res2005 6545004505
Not in our library10.1158/0008-5472.can-05-0259
49.
Weisberg E Manley PW Breitenstein W Bruggen J Cowan-Jacob SW Ray A Huntly B Fabbro D Fendrich G Hall-Meyers E Characterization of AMN107, a selective inhibitor of native and mutant Bcr-AblCancer Cell2005 7129141
Not in our library10.1016/j.ccr.2005.01.007
50.
O'Farrell AM Abrams TJ Yuen HA Ngai TJ Louie SG Yee KW Wong LM Hong W Lee LB Town A SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivoBlood2003 10135973605
Not in our library10.1182/blood-2002-07-2307
51.
Golas JM Arndt K Etienne C Lucas J Nardin D Gibbons J Frost P Ye F Boschelli DH Boschelli F SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude miceCancer Res2003 63375381
Not in our library
52.
Pricl S Fermeglia M Ferrone M Tamborini E T315I-mutated Bcr-Abl in chronic myeloid leukemia and imatinib: insights from a computational studyMol Cancer Ther2005 411671174
Not in our library10.1158/1535-7163.mct-05-0101
53.
Lee TS Potts SJ Kantarjian H Cortes J Giles F Albitar M Molecular basis explanation for imatinib resistance of BCR-ABL due to T315I and P-loop mutations from molecular dynamics simulationsCancer2008 11217441753
Not in our library10.1002/cncr.23355
54.
Shiotsu Y Kiyoi H Ishikawa Y Tanizaki R Shimizu M Umehara H Ishii K Mori Y Ozeki K Minami Y KW-2449, a novel multi-kinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocationBlood2009 11416071617
Not in our library10.1182/blood-2009-01-199307
55.
Tuma RS With targeted drugs, chronic myelogenous leukemia therapy may follow HIV's modelJ Natl Cancer Inst2007 99192194
Not in our library10.1093/jnci/djk073
56.
Roche-Lestienne C Soenen-Cornu V Grardel-Duflos N Lai JL Philippe N Facon T Fenaux P Preudhomme C Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatmentBlood2002 10010141018
Not in our library10.1182/blood.v100.3.1014
57.
Turke AB Zejnullahu K Wu YL Song Y Dias-Santagata D Lifshits E Toschi L Rogers A Mok T Sequist L Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLCCancer Cell2010 177788
Not in our library10.1016/j.ccr.2009.11.022
58.
Bachleitner-Hofmann T Sun MY Chen CT Tang L Song L Zeng Z Shah M Christensen JG Rosen N Solit DB Weiser MR HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cellsMol Cancer Ther2008 734993508
Not in our library10.1158/1535-7163.mct-08-0374
59.
Kreuzer KA Le Coutre P Landt O Na IK Schwarz M Schultheis K Hochhaus A Dorken B Preexistence and evolution of imatinib mesylate-resistant clones in chronic myelogenous leukemia detected by a PNA-based PCR clamping techniqueAnn Hematol2003 82284289
Not in our library10.1007/s00277-003-0690-5
60.
Ricci C Scappini B Divoky V Gatto S Onida F Verstovsek S Kantarjian HM Beran M Mutation in the ATP-binding pocket of the ABL kinase domain in an STI571-resistant BCR/ABL-positive cell lineCancer Res2002 6259955998
Not in our library
61.
de Silva CM Reid R Gastrointestinal stromal tumors (GIST): C-kit mutations, CD117 expression, differential diagnosis and targeted cancer therapy with ImatinibPathol Oncol Res2003 91319
Not in our library10.1007/bf03033708
62.
Braconi C Bracci R Cellerino R Molecular targets in Gastrointestinal Stromal Tumors (GIST) therapyCurr Cancer Drug Targets2008 8359366
Not in our library10.2174/156800908785133169
63.
Burgess MR Sawyers CL Treating imatinib-resistant leukemia: the next generation targeted therapiesScientificWorldJournal2006 6918930
Not in our library10.1100/tsw.2006.184
64.
Sleijfer S Wiemer E Seynaeve C Verweij J Improved insight into resistance mechanisms to imatinib in gastrointestinal stromal tumors: a basis for novel approaches and individualization of treatmentOncologist2007 12719726
Not in our library10.1634/theoncologist.12-6-719
65.
Loughrey MB Waring PM Dobrovic A Demetri G Kovalenko S McArthur G Polyclonal resistance in gastrointestinal stromal tumor treated with sequential kinase inhibitorsClin Cancer Res2006 1262056206author reply 6206-6207.
Not in our library10.1158/1078-0432.ccr-06-1079
66.
Uramoto H Mitsudomi T Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?Br J Cancer2007 96857863
Not in our library10.1038/sj.bjc.6603665
67.
Nguyen KS Kobayashi S Costa DB Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathwayClin Lung Cancer2009 10281289
Not in our library10.3816/clc.2009.n.039
68.
Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain · 2005
No notice
69.
Pillay V Allaf L Wilding AL Donoghue JF Court NW Greenall SA Scott AM Johns TG The plasticity of oncogene addiction: implications for targeted therapies directed to receptor tyrosine kinasesNeoplasia2009 11448458
Not in our library10.1593/neo.09230
70.
Engelman JA Zejnullahu K Mitsudomi T Song Y Hyland C Park JO Lindeman N Gale CM Zhao X Christensen J MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signalingScience2007 31610391043
Not in our library10.1126/science.1141478
71.
Lynch TJ Bell DW Sordella R Gurubhagavatula S Okimoto RA Brannigan BW Harris PL Haserlat SM Supko JG Haluska FG Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinibN Engl J Med2004 35021292139
Not in our library10.1056/nejmoa040938
72.
Mulloy R Ferrand A Kim Y Sordella R Bell DW Haber DA Anderson KS Settleman J Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinibCancer Res2007 6723252330
Not in our library10.1158/0008-5472.can-06-4293
73.
Engelman JA Mukohara T Zejnullahu K Lifshits E Borras AM Gale CM Naumov GN Yeap BY Jarrell E Sun J Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancerJ Clin Invest2006 11626952706
Not in our library10.1172/jci28656
74.
Haber DA Bell DW Sordella R Kwak EL Godin-Heymann N Sharma SV Lynch TJ Settleman J Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitorsCold Spring Harb Symp Quant Biol2005 70419426
Not in our library10.1101/sqb.2005.70.043
75.
Godin-Heymann N Ulkus L Brannigan BW McDermott U Lamb J Maheswaran S Settleman J Haber DA The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitorMol Cancer Ther2008 7874879
Not in our library10.1158/1535-7163.mct-07-2387
76.
Nelson MH Dolder CR Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumorsAnn Pharmacother2006 40261269
Not in our library10.1345/aph.1g387
77.
Trowe T Boukouvala S Calkins K Cutler RE Jr Fong R Funke R Gendreau SB Kim YD Miller N Woolfrey JR EXEL-7647 inhibits mutant forms of ErbB2 associated with lapatinib resistance and neoplastic transformationClin Cancer Res2008 1424652475
Not in our library10.1158/1078-0432.ccr-07-4367
78.
Heidel F Solem FK Breitenbuecher F Lipka DB Kasper S Thiede MH Brandts C Serve H Roesel J Giles F Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domainBlood2006 107293300
Not in our library10.1182/blood-2005-06-2469
79.
Cools J Mentens N Furet P Fabbro D Clark JJ Griffin JD Marynen P Gilliland DG Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemiaCancer Res2004 6463856389
Not in our library10.1158/0008-5472.can-04-2148
80.
von Bubnoff N Engh RA Aberg E Sanger J Peschel C Duyster J FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitroCancer Res2009 693032
Not in our library10.1158/0008-5472.can-08-2923
81.
Hiles JJ Kolesar JM Role of sunitinib and sorafenib in the treatment of metastatic renal cell carcinomaAm J Health Syst Pharm2008 65123131
Not in our library10.2146/ajhp060661
82.
Lierman E Michaux L Beullens E Pierre P Marynen P Cools J Vandenberghe P FIP1L1-PDGFRalpha D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRalpha T674I eosinophilic leukemia with single agent sorafenibLeukemia2009 23584551
Not in our library10.1038/leu.2009.2
83.
Kloos RT Ringel MD Knopp MV Hall NC King M Stevens R Liang J Wakely PE Jr Vasko VV Saji M Phase II Trial of Sorafenib in Metastatic Thyroid CancerJ Clin Oncol2009 2710167584
Not in our library10.1200/jco.2008.18.2717
84.
Lockwood WW Coe BP Williams AC MacAulay C Lam WL Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cell linesInt J Cancer2007 120436443
Not in our library10.1002/ijc.22335
85.
Smolen GA Sordella R Muir B Mohapatra G Barmettler A Archibald H Kim WJ Okimoto RA Bell DW Sgroi DC Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752Proc Natl Acad Sci USA2006 10323162321
Not in our library10.1073/pnas.0508776103
86.
Hellman A Zlotorynski E Scherer SW Cheung J Vincent JB Smith DI Trakhtenbrot L Kerem B A role for common fragile site induction in amplification of human oncogenesCancer Cell2002 18997
Not in our library10.1016/s1535-6108(02)00017-x
87.
Gorre ME Mohammed M Ellwood K Hsu N Paquette R Rao PN Sawyers CL Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplificationScience2001 293876880
Not in our library10.1126/science.1062538
88.
Ercan D Zejnullahu K Yonesaka K Xiao Y Capelletti M Rogers A Lifshits E Brown A Lee C Christensen JG Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitorOncogene2010 in press
Not in our library10.1038/onc.2009.526
89.
Stolzel F Steudel C Oelschlagel U Mohr B Koch S Ehninger G Thiede C Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cellsAnn Hematol2010 in press
Not in our library10.1007/s00277-009-0889-1
90.
Yano S Wang W Li Q Matsumoto K Sakurama H Nakamura T Ogino H Kakiuchi S Hanibuchi M Nishioka Y Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutationsCancer Res2008 6894799487
Not in our library10.1158/0008-5472.can-08-1643
91.
Bean J Brennan C Shih JY Riely G Viale A Wang L Chitale D Motoi N Szoke J Broderick S MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinibProc Natl Acad Sci USA2007 1042093220937
Not in our library10.1073/pnas.0710370104
92.
Khorashad JS De Melo VA Fiegler H Gerrard G Marin D Apperley JF Goldman JM Foroni L Reid AG Multiple sub-microscopic genomic lesions are a universal feature of chronic myeloid leukaemia at diagnosisLeukemia2008 2218061807
Not in our library10.1038/leu.2008.210
93.
McManus MT MicroRNAs and cancerSemin Cancer Biol2003 13253258
Not in our library10.1016/s1044-579x(03)00038-5
94.
Gregory RI Shiekhattar R MicroRNA biogenesis and cancerCancer Res2005 6535093512
Not in our library10.1158/0008-5472.can-05-0298
95.
Weiss GJ Bemis LT Nakajima E Sugita M Birks DK Robinson WA Varella-Garcia M Bunn PA Jr Haney J Helfrich BA EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell linesAnn Oncol2008 1910531059
Not in our library10.1093/annonc/mdn006
96.
Calin GA Liu CG Sevignani C Ferracin M Felli N Dumitru CD Shimizu M Cimmino A Zupo S Dono M MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemiasProc Natl Acad Sci USA2004 1011175511760
Not in our library10.1073/pnas.0404432101
97.
Mahadevan D Cooke L Riley C Swart R Simons B Della Croce K Wisner L Iorio M Shakalya K Garewal H A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumorsOncogene2007 2639093919
Not in our library10.1038/sj.onc.1210173
98.
Seike M Goto A Okano T Bowman ED Schetter AJ Horikawa I Mathe EA Jen J Yang P Sugimura H MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokersProc Natl Acad Sci USA2009 1061208512090
Not in our library10.1073/pnas.0905234106
99.
Pogribny IP Filkowski JN Tryndyak VP Golubov A Shpyleva SI Kovalchuk O Alterations of microRNAs and their targets are associated with acquired resistance of MCF-7 breast cancer cells to cisplatinInt J Cancer2010
Not in our library10.1002/ijc.25191
100.
Boren T Xiong Y Hakam A Wenham R Apte S Chan G Kamath SG Chen DT Dressman H Lancaster JM MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapyGynecol Oncol2009 113249255
Not in our library10.1016/j.ygyno.2009.01.014
101.
Sorrentino A Liu CG Addario A Peschle C Scambia G Ferlini C Role of microRNAs in drug-resistant ovarian cancer cellsGynecol Oncol2008 111478486
Not in our library10.1016/j.ygyno.2008.08.017
102.
Yang N Kaur S Volinia S Greshock J Lassus H Hasegawa K Liang S Leminen A Deng S Smith L MicroRNA microarray identifies Let-7i as a novel biomarker and therapeutic target in human epithelial ovarian cancerCancer Res2008 681030710314
Not in our library10.1158/0008-5472.can-08-1954
103.
van Jaarsveld MT Helleman J Berns EM Wiemer EA MicroRNAs in ovarian cancer biology and therapy resistanceInt J Biochem Cell Biol2010 in press
Not in our library10.1016/j.biocel.2010.01.014
104.
Hanahan D Weinberg RA The hallmarks of cancerCell2000 1005770
Not in our library10.1016/s0092-8674(00)81683-9
105.
Mahon FX Hayette S Lagarde V Belloc F Turcq B Nicolini F Belanger C Manley PW Leroy C Etienne G Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpressionCancer Res2008 6898099816
Not in our library10.1158/0008-5472.can-08-1008
106.
Li L Lin X Shoemaker AR Albert DH Fesik SW Shen Y Hypoxia-inducible factor-1 inhibition in combination with temozolomide treatment exhibits robust antitumor efficacy in vivoClin Cancer Res2006 1247474754
Not in our library10.1158/1078-0432.ccr-05-2842
107.
Pennacchietti S Michieli P Galluzzo M Mazzone M Giordano S Comoglio PM Hypoxia promotes invasive growth by transcriptional activation of the met protooncogeneCancer Cell2003 3347361
Not in our library10.1016/s1535-6108(03)00085-0
108.
Noro R Gemma A Miyanaga A Kosaihira S Minegishi Y Nara M Kokubo Y Seike M Kataoka K Matsuda K PTEN inactivation in lung cancer cells and the effect of its recovery on treatment with epidermal growth factor receptor tyrosine kinase inhibitorsInt J Oncol2007 3111571163
Not in our library
109.
Yacoub A Park MA Hanna D Hong Y Mitchell C Pandya AP Harada H Powis G Chen CS Koumenis C OSU-03012 promotes caspase-independent but PERK-, cathepsin B-, BID-, and AIF-dependent killing of transformed cellsMol Pharmacol2006 70589603
Not in our library10.1124/mol.106.025007
110.
Xia W Bacus S Hegde P Husain I Strum J Liu L Paulazzo G Lyass L Trusk P Hill J A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancerProc Natl Acad Sci USA2006 10377957800
Not in our library10.1073/pnas.0602468103
111.
McDermott U Pusapati RV Christensen JG Gray NS Settleman J Acquired Resistance of Non-Small Cell Lung Cancer Cells to MET Kinase Inhibition Is Mediated by a Switch to Epidermal Growth Factor Receptor DependencyCancer Res2010 7016251634
Not in our library10.1158/0008-5472.can-09-3620
112.
Jones HE Goddard L Gee JM Hiscox S Rubini M Barrow D Knowlden JM Williams S Wakeling AE Nicholson RI Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cellsEndocr Relat Cancer2004 11793814
Not in our library10.1677/erc.1.00799
113.
Desbois-Mouthon C Baron A Blivet-Van Eggelpoel MJ Fartoux L Venot C Bladt F Housset C Rosmorduc O Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinomaClin Cancer Res2009 1554455456
Not in our library10.1158/1078-0432.ccr-08-2980
114.
Nahta R Yuan LX Du Y Esteva FJ Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signalingMol Cancer Ther2007 6667674
Not in our library10.1158/1535-7163.mct-06-0423
115.
Jones HEGJMW Hutcheson IR Nicholson RI Growth factor pathway switching: implications for the use of gefitinib and trastuzumabBreast Cancer Online2006 9e27
Not in our library10.1017/s1470903106005451
116.
Guix M Faber AC Wang SE Olivares MG Song Y Qu S Rinehart C Seidel B Yee D Arteaga CL Engelman JA Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteinsJ Clin Invest2008 11826092619
Not in our library10.1172/jci34588
117.
Sawabu T Seno H Kawashima T Fukuda A Uenoyama Y Kawada M Kanda N Sekikawa A Fukui H Yanagita M Growth arrest-specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathwayMol Carcinog2007 46155164
Not in our library10.1002/mc.20211
118.
Ito T Tanaka H Kimura A Establishment and characterization of a novel imatinib-sensitive chronic myeloid leukemia cell line MYL, and an imatinib-resistant subline MYL-R showing overexpression of LynEur J Haematol2007 78417431
Not in our library10.1111/j.1600-0609.2007.00835.x
119.
Huang D Ding Y Zhou M Rini BI Petillo D Qian CN Kahnoski R Futreal PA Furge KA Teh BT Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinomaCancer Res2010 7010631071
Not in our library10.1158/0008-5472.can-09-3965
120.
Mizukami Y Jo WS Duerr EM Gala M Li J Zhang X Zimmer MA Iliopoulos O Zukerberg LR Kohgo Y Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cellsNat Med2005 11992997
Not in our library10.1038/nm1294
121.
Morse MA Wei J Hartman Z Xia W Ren XR Lei G Barry WT Osada T Hobeika AC Peplinski S Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivoInt J Cancer2009 in press
Not in our library10.1002/ijc.24995
122.
Adida C Berrebi D Peuchmaur M Reyes-Mugica M Altieri DC Anti-apoptosis gene, survivin, and prognosis of neuroblastomaLancet1998 351882883
Not in our library10.1016/s0140-6736(05)70294-4
123.
Saitoh Y Yaginuma Y Ishikawa M Analysis of Bcl-2, Bax and Survivin genes in uterine cancerInt J Oncol1999 15137141
Not in our library10.3892/ijo.15.1.137
124.
Ambrosini G Adida C Sirugo G Altieri DC Induction of apoptosis and inhibition of cell proliferation by survivin gene targetingJ Biol Chem1998 2731117711182
Not in our library10.1074/jbc.273.18.11177
125.
Lu CD Altieri DC Tanigawa N Expression of a novel antiapoptosis gene, survivin, correlated with tumor cell apoptosis and p53 accumulation in gastric carcinomasCancer Res1998 5818081812
Not in our library
126.
Konno R Yamakawa H Utsunomiya H Ito K Sato S Yajima A Expression of survivin and Bcl-2 in the normal human endometriumMol Hum Reprod2000 6529534
Not in our library10.1093/molehr/6.6.529
127.
Endoh A Yagihashi A Asanuma K Moriai R Izawa A Koyanagi Y Sato T Kobayashi D Watanabe N Hematopoietic progenitor cell counts performed by the Sysmex SE-9000 analyzer can guide timing of peripheral blood stem cell harvestAnticancer Res2001 21601604
Not in our library
128.
Gimenez-Bonafe P Tortosa A Perez-Tomas R Overcoming drug resistance by enhancing apoptosis of tumor cellsCurr Cancer Drug Targets2009 9320340
Not in our library10.2174/156800909788166600
129.
Gillet JP Gottesman MM Mechanisms of multidrug resistance in cancerMethods Mol Biol2010 5964776full_text
Not in our library10.1007/978-1-60761-416-6_4
130.
Tao LY Liang YJ Wang F Chen LM Yan YY Dai CL Fu LW Cediranib (recentin, AZD2171) reverses ABCB1- and ABCC1-mediated multidrug resistance by inhibition of their transport functionCancer Chemother Pharmacol2009 6459619
Not in our library10.1007/s00280-009-0949-1
131.
Dai CL Liang YJ Wang YS Tiwari AK Yan YY Wang F Chen ZS Tong XZ Fu LW Sensitization of ABCG2-overexpressing cells to conventional chemotherapeutic agent by sunitinib was associated with inhibiting the function of ABCG2Cancer Lett2009 27917483
Not in our library10.1016/j.canlet.2009.01.027
132.
Turk D Szakacs G Relevance of multidrug resistance in the age of targeted therapyCurr Opin Drug Discov Devel2009 12246252
Not in our library
133.
Mahon FX Belloc F Lagarde V Chollet C Moreau-Gaudry F Reiffers J Goldman JM Melo JV MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line modelsBlood2003 10123682373
Not in our library10.1182/blood.v101.6.2368
134.
Che XF Nakajima Y Sumizawa T Ikeda R Ren XQ Zheng CL Mukai M Furukawa T Haraguchi M Gao H Reversal of P-glycoprotein mediated multidrug resistance by a newly synthesized 1,4-benzothiazipine derivative, JTV-519Cancer Lett2002 187111119
Not in our library10.1016/s0304-3835(02)00359-2
135.
Kotaki M Motoji T Takanashi M Wang YH Mizoguchi H Anti-proliferative effect of the abl tyrosine kinase inhibitor STI571 on the P-glycoprotein positive K562/ADM cell lineCancer Lett2003 1996168
Not in our library10.1016/s0304-3835(03)00338-0
136.
Rumpold H Wolf AM Gruenewald K Gastl G Gunsilius E Wolf D RNAi-mediated knockdown of P-glycoprotein using a transposon-based vector system durably restores imatinib sensitivity in imatinib-resistant CML cell linesExp Hematol2005 33767775
Not in our library10.1016/j.exphem.2005.03.014
137.
Widmer N Rumpold H Untergasser G Fayet A Buclin T Decosterd LA Resistance reversal by RNAi silencing of MDR1 in CML cells associated with increase in imatinib intracellular levelsLeukemia2007 2115611562author reply 1562-1564.
Not in our library10.1038/sj.leu.2404671
138.
Hiwase DK Saunders V Hewett D Frede A Zrim S Dang P Eadie L To LB Melo J Kumar S Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implicationsClin Cancer Res2008 1438813888
Not in our library10.1158/1078-0432.ccr-07-5095
139.
Shukla S Robey RW Bates SE Ambudkar SV Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2Drug Metab Dispos2009 37359365
Not in our library10.1124/dmd.108.024612
140.
Elkind NB Szentpetery Z Apati A Ozvegy-Laczka C Varady G Ujhelly O Szabo K Homolya L Varadi A Buday L Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD Gefitinib)Cancer Res1839 6517701777
Not in our library10.1158/0008-5472.can-04-3303
141.
Thomas J Wang L Clark RE Pirmohamed M Active transport of imatinib into and out of cells: implications for drug resistanceBlood2004 10437393745
Not in our library10.1182/blood-2003-12-4276
142.
White DL Saunders VA Dang P Engler J Zannettino AC Cambareri AC Quinn SR Manley PW Hughes TP OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinibBlood2006 108697704
Not in our library10.1182/blood-2005-11-4687
143.
Wang L Giannoudis A Lane S Williamson P Pirmohamed M Clark RE Expression of the uptake drug transporter hOCT1 is an important clinical determinant of the response to imatinib in chronic myeloid leukemiaClin Pharmacol Ther2008 83258264
Not in our library10.1038/sj.clpt.6100268
144.
Gambacorti-Passerini C Barni R le Coutre P Zucchetti M Cabrita G Cleris L Rossi F Gianazza E Brueggen J Cozens R Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571J Natl Cancer Inst2000 9216411650
Not in our library10.1093/jnci/92.20.1641
145.
Gambacorti-Passerini C Zucchetti M Russo D Frapolli R Verga M Bungaro S Tornaghi L Rossi F Pioltelli P Pogliani E Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patientsClin Cancer Res2003 9625632
Not in our library
146.
le Coutre P Kreuzer KA Na IK Lupberger J Holdhoff M Appelt C Schwarz M Muller C Gambacorti-Passerini C Platzbecker U Determination of alpha-1 acid glycoprotein in patients with Ph+ chronic myeloid leukemia during the first 13 weeks of therapy with STI571Blood Cells Mol Dis2002 287585
Not in our library10.1006/bcmd.2002.0493
147.
Allegra CJ Jessup JM Somerfield MR Hamilton SR Hammond EH Hayes DF McAllister PK Morton RF Schilsky RL American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapyJ Clin Oncol2009 2720912096
Not in our library10.1200/jco.2009.21.9170
148.
Lievre A Bachet JB Le Corre D Boige V Landi B Emile JF Cote JF Tomasic G Penna C Ducreux M KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancerCancer Res2006 6639923995
Not in our library10.1158/0008-5472.can-06-0191
149.
De Roock W Piessevaux H De Schutter J Janssens M De Hertogh G Personeni N Biesmans B Van Laethem JL Peeters M Humblet Y KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximabAnn Oncol2008 19508515
Not in our library10.1093/annonc/mdm496
150.
Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy · 2007
No notice
151.
Di Nicolantonio F Martini M Molinari F Sartore-Bianchi A Arena S Saletti P De Dosso S Mazzucchelli L Frattini M Siena S Bardelli A Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancerJ Clin Oncol2008 2657055712
Not in our library10.1200/jco.2008.18.0786
152.
Berns K Horlings HM Hennessy BT Madiredjo M Hijmans EM Beelen K Linn SC Gonzalez-Angulo AM Stemke-Hale K Hauptmann M A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancerCancer Cell2007 12395402
Not in our library10.1016/j.ccr.2007.08.030
153.
PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients · 2007
No notice
154.
Perrone F Lampis A Orsenigo M Di Bartolomeo M Gevorgyan A Losa M Frattini M Riva C Andreola S Bajetta E PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patientsAnn Oncol2009 208490
Not in our library10.1093/annonc/mdn541
155.
Nagata Y Lan KH Zhou X Tan M Esteva FJ Sahin AA Klos KS Li P Monia BP Nguyen NT PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patientsCancer Cell2004 6117127
Not in our library10.1016/j.ccr.2004.06.022
156.
PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer · 2006
No notice
157.
Bardelli A Siena S Molecular Mechanisms of Resistance to Cetuximab and Panitumumab in Colorectal CancerJ Clin Oncol2010 287125461
Not in our library10.1200/jco.2009.24.6116
158.
Lu Y Zi X Pollak M Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cellsInt J Cancer2004 108334341
Not in our library10.1002/ijc.11445
159.
Nahta R Yuan LX Zhang B Kobayashi R Esteva FJ Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cellsCancer Res2005 651111811128
Not in our library10.1158/0008-5472.can-04-3841
160.
Lu Y Zi X Zhao Y Mascarenhas D Pollak M Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin)J Natl Cancer Inst2001 9318521857
Not in our library10.1093/jnci/93.24.1852
161.
Shattuck DL Miller JK Carraway KL Sweeney C Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cellsCancer Res2008 6814711477
Not in our library10.1158/0008-5472.can-07-5962
162.
Sok JC Coppelli FM Thomas SM Lango MN Xi S Hunt JL Freilino ML Graner MW Wikstrand CJ Bigner DD Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targetingClin Cancer Res2006 1250645073
Not in our library10.1158/1078-0432.ccr-06-0913
163.
Lu Y Li X Liang K Luwor R Siddik ZH Mills GB Mendelsohn J Fan Z Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximabCancer Res2007 6782408247
Not in our library10.1158/0008-5472.can-07-0589
164.
Puri N Salgia R Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancerJ Carcinog2008 79
Not in our library10.4103/1477-3163.44372
165.
Wheeler DL Iida M Kruser TJ Nechrebecki MM Dunn EF Armstrong EA Huang S Harari PM Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximabCancer Biol Ther2009 8696703
Not in our library10.4161/cbt.8.8.7903
166.
Valabrega G Montemurro F Sarotto I Petrelli A Rubini P Tacchetti C Aglietta M Comoglio PM Giordano S TGFalpha expression impairs Trastuzumab-induced HER2 downregulationOncogene2005 2430023010
Not in our library10.1038/sj.onc.1208478
167.
Casanovas O Hicklin DJ Bergers G Hanahan D Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumorsCancer Cell2005 8299309
Not in our library10.1016/j.ccr.2005.09.005
168.
Fischer C Jonckx B Mazzone M Zacchigna S Loges S Pattarini L Chorianopoulos E Liesenborghs L Koch M De Mol M Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vesselsCell2007 131463475
Not in our library10.1016/j.cell.2007.08.038
169.
Ridgway J Zhang G Wu Y Stawicki S Liang WC Chanthery Y Kowalski J Watts RJ Callahan C Kasman I Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesisNature2006 44410831087
Not in our library10.1038/nature05313
170.
Kopetz S Hoff PM Morris JS Wolff RA Eng C Glover KY Adinin R Overman MJ Valero V Wen S Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistanceJ Clin Oncol2010 28453459
Not in our library10.1200/jco.2009.24.8252
171.
Loges S Schmidt T Carmeliet P Mechanisms of Resistance to Anti-Angiogenic Therapy and Development of Third-Generation Anti-Angiogenic Drug CandidatesGenes & Cancer2010 11225
Not in our library10.1177/1947601909356574
172.
Price-Schiavi SA Jepson S Li P Arango M Rudland PS Yee L Carraway KL Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistanceInt J Cancer2002 99783791
Not in our library10.1002/ijc.10410
173.
Nagy P Friedlander E Tanner M Kapanen AI Carraway KL Isola J Jovin TM Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell lineCancer Res2005 65473482
Not in our library
174.
Haura EB Tanvetyanon T Chiappori A Williams C Simon G Antonia S Gray J Litschauer S Tetteh L Neuger A Phase I/II Study of the Src Inhibitor Dasatinib in Combination With Erlotinib in Advanced Non-Small-Cell Lung CancerJ Clin Oncol2010 288138794
Not in our library10.1200/jco.2009.25.4029
175.
Kim HP Han SW Kim SH Im SA Oh DY Bang YJ Kim TY Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cellsMol Cancer Ther2008 7607615
Not in our library10.1158/1535-7163.mct-07-2068
176.
Park SJ Kim MJ Kim YK Kim SM Park JY Myoung H Combined cetuximab and genistein treatment shows additive anti-cancer effect on oral squamous cell carcinomaCancer Lett2009 in press
Not in our library10.1016/j.canlet.2009.11.004

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Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management · 2023
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Combination erlotinib-cisplatin and Atg3-mediated autophagy in erlotinib resistant lung cancer. · 2012
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Efficient Blockade of Akt signaling is a determinant factor to overcome resistance to Matuzumab · 2011
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