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Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications

Teresa Helsten, Maria Schwaederle, Razelle Kurzrock

Cancer and Metastasis Reviews · 2015 · Review

doi:10.1007/s10555-015-9579-8

Abstract

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are transmembrane growth factor receptors with wide tissue distribution. FGF/FGFR signaling is involved in neoplastic behavior and also development, differentiation, growth, and survival. FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3), and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2); intriguingly, some of these activating FGFR mutations are also seen in human cancers. FGF/FGFR aberrations reported in cancers are mainly thought to be gain-of-function changes, and several cancers have high frequencies of FGFR alterations, including breast, bladder, or squamous cell carcinomas (lung and head and neck). FGF ligand aberrations (predominantly gene amplifications) are also frequently seen in cancers, in contrast to hereditary syndromes. There are several pharmacologic agents that have been or are being developed for inhibition of FGFR/FGF signaling. These include both highly selective inhibitors as well as multi-kinase inhibitors. Of note, only four agents (ponatinib, pazopanib, regorafenib, and recently lenvatinib) are FDA-approved for use in cancer, although the approval was not based on their activity against FGFR. Perturbations in the FGFR/FGF signaling are present in both inherited and malignant diseases. The development of potent inhibitors targeting FGF/FGFR may provide new tools against disorders caused by FGF/FGFR alterations.

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.

Introduction

One of the most important advances in tumor biology is the recognition that cancer is frequently driven by inherited or acquired alterations in specific gene(s) or their products. Genomic alterations include changes in expression that can result from mutation, deletion, gene amplification, and/or translocation. Complicating matters, cancers often harbor multiple genetic alterations, but one or a few of these are thought to be primarily responsible for neoplastic behavior in any given tumor. These are the so-called “driver mutations,” while “passenger mutations” may have a more nuanced impact. A literature review suggests that over 1 % of human genes can be implicated as cancer drivers when they are mutated, with protein kinases comprising the largest subgroup of genes altered.

Among human signaling pathways, fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) is one of the pathways most enriched in non-synonymous mutations, including several candidate driver mutations. A computational method designed to identify driver mutations within protein kinase datasets successfully identified multiple aberrations in the FGF/FGFR machinery. In keeping with other genes implicated in neoplastic behavior, FGF/FGFR signaling is also involved in development, differentiation, growth, and survival mechanisms. Indeed, FGFR aberrations have been identified in both hereditary and neoplastic human diseases.

Most of the reported FGFR mutations that cause heritable human diseases are activating mutations which increase receptor signaling. These abnormalities are seen in craniofacial and skeletal syndromes such as the craniosynostoses (Pfeiffer, Crouzon, Apert, Jackson-Weiss, Muenke, and Beare-Stevenson syndromes) and dwarfism syndromes (achondroplasia, thanatophoric dysplasia, and hypochondroplasia). The only reported inherited condition caused by loss of FGFR function is an autosomal dominant form of hereditary hypogonatotrophic hypogonadism 2 with or without anosmia, which is caused by loss of function of FGFR1 or a missense mutation in FGF8. Intriguingly, some of the same activating FGFR mutations seen in inherited syndromes are also seen in human cancers. Furthermore, FGF/FGFR aberrations reported in cancers are overwhelmingly thought to be gain-of-function changes, including gene amplifications and gene rearrangements.

The goal of identification and characterization of driver mutations in cancer is, ultimately, to create successful anti-cancer therapies with which to prosecute these tumors; several such therapies already exist, demonstrating proof of principle. Furthermore, for some gene targets, drugs may impact the course of cancer as well as non-malignant conditions that are driven by abnormalities in the cognate signal. JAK2 aberrations, for instance, are found in myelofibrosis, and JAK2 inhibitors such as ruxolitinib provide significant benefit in such patients. At the same time, the JAK2 inhibitor tofacitinib can benefit patients with rheumatoid arthritis and is approved for that indication. In the case of FGF/FGFR, multiple drugs targeting this pathway have entered the clinic. Herein, we discuss the landscape of diseases that are driven by aberrant FGF/FGFR machinery.

Molecular biology of FGF/FGFR signaling

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are evolutionarily conserved transmembrane growth factor receptors with wide tissue distribution in all vertebrates. FGFs and FGFRs share homologies among their respective groups and with other signaling molecules. FGFRs in particular are similar to other signaling receptors, including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and other receptor tyrosine kinases. However, there are important differences between the individual signaling molecules that allow for precise control of a full range of processes, including development, cell survival, differentiation, motility, angiogenesis, and carcinogenesis.

Receptors

In humans, there are five known FGFRs, called FGFR1–FGFR4 and FGFRL1 (also known as FGFR5). FGFR1–FGFR4 are typical growth factor receptor tyrosine kinases, with extracellular immunoglobulin (Ig)-like domains and intracellular tyrosine kinase domains, while FGFRL1 lacks the intracellular kinase domain and has less clear function(s). Upon binding of their ligands, the typical receptors homo- or hetero-dimerize, leading to sequential phosphorylation of specific intracellular tyrosine residues and activation of an intracellular signaling cascade and gene transcription (Fig. 1). The FGFR signaling pathway interacts with several other important intracellular pathways, including PI3K/Akt, Wnt, hedgehog, and bone morphogenic protein (BMP). FGFR1–4 have different ligand specificities based on developmental aspects, tissue distribution, and RNA splicing variation. For example, the FGFR2b isoform is predominantly expressed in epithelial cells, while the FGFR2c isoform is expressed predominantly in mesenchymal cells, and switching from FGFR2b to FGFR2c occurs during progression and invasion of prostate and bladder cancers.

Ligands

There are 18 human ligands for FGFRs (Fig. 1). They are FGF1 (acidic FGF), FGF2 (basic FGF), FGF3, FGF4, FGF5, FGF6, FGF7 (KGF), FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF19, FGF20, FGF21, FGF22, and FGF23. FGF11–14 are not ligands for FGFRs and are known as FGF homologous factors (FHF1–4). There is no human FGF15 (FGF15 is the mouse equivalent of human FGF19). The FGFR ligands are secreted proteins that bind to the extracellular matrix, thereby restricting their influence to the tissue where they are produced (autocrine or paracrine function). However, three of the FGFs—FGF19, FGF21, and FGF23—bind less tightly to extracellular matrix heparin sulfates, so they are able to act systemically in an endocrine fashion (hormone-like), allowing them to spread from their production site into the circulation. Most FGFs are secreted proteins with cleavable amino terminal portions, but FGF9, FGF16, and FGF20 have non-cleavable secretion sequences, and FGF1 and FGF2 have no secretion sequences, although they are found in the extracellular compartment, suggesting an alternate process of release. Most FGFs are released from binding to the extracellular matrix via action of heparin sulfate proteoglycans and/or fibroblast growth factor–binding protein (FGFBP1).

FGF/FGFR interaction and function

In general, FGFs are promiscuous, and most can bind to any of the four main FGFRs, although some of the FGF/FGFR ligand/receptor pairs differ in their affinities (Fig. 1c). FGFs interact with cell surface heparan sulfate proteoglycans (HSPGs) and with the transmembrane protein Klotho (for the hormone-like FGF19, 20, 23) to stabilize binding to FGFRs. Ornitz et al. systemically investigated affinities of FGFs for each FGFR isoform and showed, for example, that FGFR2b is a high-affinity receptor for FGF1, FGF7, FGF10, and FGF22, while FGFR2c has high affinity for FGF1, FGF2, FGF4, FGF6, FGF8, FGF9, and FGF20. But, differential expression of either FGFs or FGFRs in time or tissue may also contribute to tissue-specific effects of FGF/FGFR signaling. For example, FGF1 and FGF2 are expressed in both embryonic and adult tissues, while FGF7–FGF9 are predominantly expressed in developing or in restricted adult tissues.

The differences in activity/function of the different FGF/FGFR pairs are also highlighted by murine gene knockout experiments. Mice heterozygous for FGFR knockout mutations develop normally, so haplo-insufficiency is not likely to be a factor. However, mice homozygous for FGFR1 or FGFR2 null mutations die in utero, and FGFR3-null mice develop normally other than overgrowth of cancellous bones and deafness. Most of the FGFs have also been knocked out in mouse models, with varying phenotypic effects, including lethality (FGF4, FGF8, FGF9, FGF10, FGF19, FGF18, and FGF23), defects in neuromusculoskeletal development or function (FGF2, FGF3, FGF6, FGF7, FGF12, FGF14, FGF17, FGF18), cardiac defects (FGF2, FGF9, FGF16, FGF19), and no identifiable abnormality (FGF1).

Activation of signaling

To signal, FGFs have to be released from the extracellular matrix by heparinases, proteases, or specific fibroblast growth factor–binding protein (FGFBP1). FGFBP1 are secreted heparin proteins that reversibly bind FGF1 and FGF2, releasing them from the extracellular matrix and increasing the local levels of free ligand available for receptor binding. FGFBP1 is secreted by keratinocytes and human epidermal carcinomas, particularly squamous cell carcinomas. Its expression is seen in development, wound healing, cancer, and angiogenesis, and it is downregulated by pharmacologic agents in vitro. The fibronectin-leucine-rich transmembrane protein 3 (FLRT3) is co-expressed with FGF8 during development, co-immunoprecipitates with FGF8/FGFRs, physically interacts with FGFRs via its fibronectin type III domain, and increases activity through the MAPK pathway, facilitating FGFR signaling.

Inhibition of signaling

FGF/FGFR signaling is negatively regulated by several mechanisms. FGFR stimulation activates sprouty proteins (SPRY1–4), which in turn negatively feedbacks on FGF/FGFR/MAPK signaling by interacting with growth factor receptor bound protein 2 (GRB2), son of sevenless homolog 1 (SoS1), and/or RAF proto-oncogene serine/threonine-protein kinase (RAF1). Intriguingly, sprouty proteins are thought to be general inhibitors of receptor tyrosine kinase growth factor signaling via inhibition of Ras-MAPK signaling, but their behavior differs among specific growth factor receptors. For example, sprouty protein inhibits FGFR signaling but potentiates epidermal growth factor receptor (EGFR) signaling. The cytoplasmic domain of similar expression to FGF (SEF, also known as IL-17 receptor D) interacts with the cytoplasmic domain of FGFR and inhibits downstream signaling of the pathway. Finally, MAP kinase phosphatases (MKPs) dephosphorylate ERKs and thereby downregulate the signaling pathway. MKP3 functions within the cytoplasm, whereas MKP1 is localized in the nucleus.

FGFRL1 is the atypical receptor that lacks an intracellular kinase domain. Like the other FGFRs, it is found in all vertebrates, is expressed in a wide variety of tissues, and binds to some FGF ligands. In vitro experiments show that FGFRL1 binds FGF3, FGF4, FGF8, FGF10, and FGF22, but not the other FGFs tested. Unlike FGFR1–4, it is shed from cell membranes, suggesting that it may serve as a ligand trap to negatively regulate signaling. Other regulatory mechanisms might include heterodimerization with other FGFRs to prevent trans-autophophorylation and thereby negatively regulating intracellular signaling or by increasing membrane turnover rates of the other FGFRs, but there is currently no evidence that these mechanisms exist. The exact functions of FGFRL1 are not known. FGFRL1-null mice die in infancy with diaphragmatic defects and renal agenesis, and there are case reports of FGFRL1 mutations in human disease: craniosynostosis and ovarian cancer.

Inherited syndromes

Several types of inherited syndromes are due to germline aberrations in FGFR. These include craniosynostosis syndromes and achondroplasia, mainly due to gain-of-function mutations, as well as loss-of-function anomalies associated with congenital hypogonadotropic hypogonadism (Table 1). Interestingly, although some of these aberrations are identical to those that, in somatic form, are associated with cancer, for the most part, the individuals with these hereditary syndromes have not been reported to have an increased incidence of cancer. Apart from case reports, there is no epidemiologic evidence that people with craniosynostosis, dwarfism, or congenital hypogonadotropic hypogonadism are at increased risk for malignancy. This is possibly related to differential effects of activating FGFR mutations in cell or tissue type in the context of stage of development. It is possible, for instance, that there are as yet unknown anti-neoplastic compensatory effects in individuals with these disorders, perhaps stemming from the presence of germline FGFR aberrations during development as opposed to the appearance of somatic FGFR mutations in human cancers.

Somatic aberrations in benign conditions

Somatic or acquired mutations in FGFR3 have been observed in benign skin conditions like seborrheic keratosis and epidermal nevi. These aberrations are activating and, when evaluated, are not seen in adjacent normal skin. Many of these are identical to mutations that are also seen in bladder and/or cervical cancers.

Somatic aberrations in malignancies

Aberrations in FGFR and its ligands are common in malignancy (Tables 2, 3, and 4 and Figs. 2 and 3). Across malignancies, FGF anomalies are found in ≈14 % and FGFR in ≈7 % of malignancies (FGF/FGFR in about 20 %).

FGFR alterations

While almost any FGFR genes can be altered in many cancer types, some acquired genetic aberrations are more striking in prevalence or in cancer type(s) than others. The most common abnormalities reported to date are gene amplifications of FGFR1–3 (Table 2). These are generally assumed to represent activation or gain-of-function amplifications, but full molecular characterization of the effects of gene amplification within specific cellular or cancer microenvironment contexts is not fully available. The cancers in which FGFR gene amplifications are most frequent include bladder urothelial carcinomas (FGFR1), squamous cell lung cancer (FGFR1), head and neck squamous cell cancer (FGFR1), uterine carcinosarcoma (FGFR3), breast adenocarcinoma (FGFR1), and gastric adenocarcinoma (FGFR2) (Tables 2 and 3, and Fig. 2). In fact, FGFR2 was first identified in a gastric cancer cell line, and it is preferentially amplified/overexpressed in the diffuse type of gastric cancer, which correlates with poor prognosis, at least in a Japanese population. More commonly, however, mutations in FGFR3 characterize bladder carcinoma. Indeed, activating mutations of fibroblast growth factor receptor-3 (FGFR3) have been described in approximately 75 % of low-grade papillary bladder tumors. In muscle-invasive disease, FGFR3 mutations are found in 20 % of tumors, but overexpression of FGFR3 is observed in about half of cases.

Loss-of-function alterations are relatively uncommon in cancer (a pattern that is also seen in hereditary disorders). However, there is at least one report indicating that some melanoma cell lines demonstrate FGFR2 loss of function.

FGFR1 amplification is prevalent in both squamous cell carcinoma of the lung and of the head and neck, suggesting a possible common underlying mechanism of carcinogenesis in these smoking-related carcinomas. Perhaps more importantly, development of FGFR1 inhibitors represents a viable targeted therapy for use in squamous cell lung cancers.

FGF alterations

FGF abnormalities are for the most part amplifications (Fig. 3 and Table 4). There are few reported data regarding the mechanism(s) of action of these amplifications. Nevertheless, it seems reasonable to hypothesize that abundance of ligand could lead to increased receptor signaling, but the reality may be more complex, perhaps relating to the stoichiometric proportions of the different ligands present. Of note, three of the ligands, FGF3, FGF4, and FGF19, are frequently co-amplified on 11q13. This amplicon is present in several cancers, including breast, bladder, and squamous cell carcinoma of the lung and head and neck (Fig. 3 and Table 4).

FGFR rearrangements

Chromosomal translocation gives rise to chimeric gene products with aberrant function (Table 2). In general, fusion gene proteins result from the fusion of a “partner gene” with a tyrosine kinase domain derived from the FGFR family member gene. As a result of their constant dimerization state, they are constitutively active in the absence of ligand. The FGFR1 gene can be fused to other genes including BCR, ZNF198, CEP110, FGFR1OP1, FGFR1OP2, HERVK, TRIM24, LRRFIP1, and MYO18A, in the 8p11 myeloproliferative syndrome manifested by myeloproliferative neoplasms and peripheral blood eosinophilia without basophilia; it is fused to the FOXO1 gene in alveolar rhabdomyosarcoma, and the FOXO1-FGFR1 fusion gene is amplified. The FGFR3 gene is fused to the MMSET gene as a result of a t(4;14)(p16.3;q32) chromosomal translocation in 10–20 % of multiple myeloma; it is fused to the ETV6 gene in peripheral T cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation. In glioblastoma multiforme, FGFR1 and FGFR3 genes are fused to neighboring TACC1 and TACC3 genes due to interstitial deletions, respectively.

FDA approved drugs that target FGFR

Only four drugs (ponatinib, regorafenib, pazopanib, and more recently lenvatinib) are FDA-approved for use in human cancers (Table 5). Ponatinib is a multi-tyrosine kinase inhibitor that was approved for imatinib-resistant chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (CP) acute lymphoblastic leukemia (ALL). The efficacy results demonstrated a 54 % major cytogenetic response (MCyR) rate in patients with CP-CML, and seventy percent of patients with CP-CML with the T315I mutation in BCR-ABL achieved MCyR. In addition of targeting BCR-ABL, ponatinib can also inhibit members of the VEGFR, PDGFR, FGFR (IC50 = 2 nM for FGFR1), and SRC families of kinases, KIT, or RET, with IC50 between 0.1 and 20 nM. Of note, ponatinib was briefly taken off the market by the FDA because of concerns about cardiovascular side effects (clotting), but soon after, it was returned to the market with updated safety monitoring recommendations. Regorafenib was approved for imatinib-resistant gastrointestinal stromal tumor (GIST) and metastatic colorectal cancer, based on a statistically significant survival prolongation observed in patients randomized to receive regorafenib (6.4 vs 5.0 months in the placebo arm, P = 0.01). Regorafenib, and its active metabolites inhibit multiple membrane-bound and intracellular kinases including those in the RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-α and -β, FGFR1-2, and Abl pathways. Pazopanib was approved for advanced renal cell carcinoma (based on a progression-free survival of 9.2 months compared to 4.2 months in the placebo arm), as well as soft tissue sarcomas (improved progression-free survival: 4.6 months versus 1.6 for patients who received placebo). Pazopanib is a multi-tyrosine kinase inhibitor whose targets include VEGFR1-3, PDGFR-α and -β, FGFR-1 and -3, and KIT. Lastly, lenvatinib is a multi-kinase inhibitor (targets including VEGFR1–3, FGFR1–4, PDGFR-α, KIT, and RET) indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. The recent approval in February 2015 was based on an improved progression-free survival (18.3 vs 3.6 months in the placebo group, P < 0.001). The approvals of these four agents (ponatinib, regorafenib, pazopanib, and lenvatinib), all three of which are multi-kinase inhibitors, were not based on activity against FGFR. Of interest, nintedanib is an FGFR inhibitor that is FDA-approved for a non-cancer indication—idiopathic pulmonary fibrosis (Table 5).

Experimental agents that target FGF/FGFR

There are several pharmacologic agents that have been or are being developed for inhibition of FGFR via targeting of the ATP binding site of the intracellular tyrosine kinase domain(s) (Table 5). The inhibition varies by their affinities for FGFR signaling, as most of these molecules are promiscuous kinase inhibitors (inhibiting VEGF, PDGF, and many other TKIs in addition to FGFR). Figure 1b gives examples of selective versus non-selective FGFR inhibitors. Of note, the dual kinase inhibitor (VEGFR/FGFR) lucitanib has shown activity in FGFR1-amplified breast cancer, with an overall response rate of 50 %. There are also selective tyrosine kinase inhibitors (TKIs) available (Table 5 and Fig. 1b). While several of these agents are currently in clinical trials, none of the more highly selective FGFR inhibitors (e.g., BGJ398 or AZD4547) are currently FDA-approved. A recent study demonstrated that Debio 1347 (a selective orally available FGFR1–3 inhibitor) displayed preferential anti-tumor activity against cells with FGFR genetic alterations in a panel of 327 cancer cell lines and xenograft models. Debio 1347 is currently under investigation for the treatment of patients harboring FGFR genetic alterations.

Of interest, other types of agents have been developed. As an example, FP-1039 is a soluble fusion protein, consisting of the extracellular domains of human FGFR1 linked to the Fc region of the human immunoglobulin G1; it is designed to bind multiple FGF ligands (TRAP molecule).

A large number of other drugs and indications are being pursued. Some FGFR inhibitors have failed to meet their phase III endpoints (Table 5). The majority of the failed trials, however, have been performed in patient populations that were not biomarker-selected.

Resistance mechanisms

In a recent phase 1 study reporting on patients with FGFR1-amplified (identified by fluorescent/chromogenic in situ hybridization) advanced or metastatic lung squamous cell carcinoma (SCC) treated with the selective pan-FGFR inhibitor BGJ398, only a limited number of patients achieved relatively short-lived partial responses (2 of 17 patients, 11.7 %); responses lasted 3 and 8 months. These observations suggest the existence of resistance mechanisms. Sohl et al. reported that resistance mutations at the “gatekeeper” residue may arise (FGFR1 V561M mutation confers a 38-fold increase in autophosphorylation and significant resistance to lucitanib), leading to tumor progression and explaining the non-durable responses. For instance, it has also been shown that the heterozygous gatekeeper mutation FGFR3 V555M appeared as a mechanism of acquired resistance to selective FGFR inhibitors. Several other activating mutations were identified in FGFR2-expressing cells treated with high concentrations of dovitinib, and the multi-kinase inhibitor ponatinib inhibitory activity was affected by the V565I gatekeeper mutation. In addition, a previously undescribed FGFR3 variant was identified as a key contributor to resistance in the MGH156-1A cell line derived from a patient with acquired resistance to EGFR TKIs, and follow-up studies clearly indicated that FGFR inhibitors re-sensitized these cells to EGFR inhibitors.

Besides secondary mutations in the kinase domain, resistance to FGFR kinase inhibitors may also occur through activation of alternative signaling pathways, as demonstrated by Harbinski et al. who showed a broad and versatile potential for tyrosine kinase receptor from the FGFR, HER, and MET family to compensate for each other. Javidi-Sharifi et al. suggest that some patients with gastrointestinal stromal tumor (GIST) treated with imatinib can develop a functional dependence on FGFR3, illustrated by the fact that the addition of the FGFR3 ligand FGF2 to GIST cells restored KIT phosphorylation during imatinib treatment. Furthermore, signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib. FGFR amplification and overexpression have also been related to poor prognosis and endocrine resistance in breast cancer. Of note, relationships between cyclins and FGF/FGFRs have also been reported at the protein level. For instance, a study showed that FGFR4 contributed to the maintenance of CCND1 via the mTOR translation pathway, and several other studies demonstrated cooperation between FGFR and CCND1. Finally, most patients with advanced cancer have complex molecular portfolios, and hence there may be multiple genomic drivers that are active and supplant the role of FGFR. In that context, it appears evident that identification of resistance mechanisms is crucial to crafting effective drug combinations.

Conclusion

The FGF/FGFR pathway is crucial to a variety of human diseases. There are five known FGFRs, FGFR1–FGFR4 and FGFRL1, and 18 human ligands for FGFRs. FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3) and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2). Loss-of-function mutations in FGF signaling are seen in congenital hypogonadotropic hypogonadism (including the Kallman syndrome variant with anosmia). Interestingly, many of the aberrations that cause the inherited skeletal disorders are also seen in human cancers.

The most common abnormalities in malignancies are gene amplifications of FGFR1–3 or of the FGF ligands. The cancers in which FGFR gene amplifications are most frequent include squamous cell lung cancer (FGFR1), head and neck squamous cell cancer (FGFR1), bladder (transitional cell) cancer (FGFR1), endometrial cancer (FGFR1), gastric adenocarcinoma (FGFR2), breast adenocarcinoma (FGFR1), and prostate adenocarcinoma (FGFR1). Point mutations are seen in all FGFRs but are less frequent in FGFs. For instance, mutations in FGFR3 are frequent in bladder carcinoma, and FGFR2 mutations in endometrial cancer, melanoma, and gastric tumors (Tables 2 and 3).

Interestingly, somatic mutations in FGFR3 have been observed in benign skin conditions such as seborrheic keratosis and epidermal nevi (but not in adjacent normal skin). FGFR rearrangements are also observed in certain cancers and characterize certain myeloproliferative disorders (Table 2).

Importantly, there are several pharmacologic agents that have been or are being developed for inhibition of FGFR kinases. These include both highly selective inhibitors as well as multi-kinase inhibitors. Ponatinib, regorafenib, pazopanib, and lenvatinib are already FDA-approved for cancer, albeit not on the basis of their FGFR activity. Very few studies in cancer have been aimed at an FGFR biomarker-selected population, and several of the FGFR inhibitors have failed phase III studies in unselected patients. A multi-kinase inhibitor (nintedanib), which suppresses FGFR1–3, was also recently FDA-approved for idiopathic pulmonary fibrosis.

Whether or not FGFR inhibitors could also be used to moderate the phenotype of inherited disorders due to FGFR activation is an intriguing question. Of interest, Garcia et al. injected ia mouse model of achondroplasia with a soluble form of human FGFR3 (acting as a decoy receptor and preventing FGF from binding to mutant FGFR3), and effective maturation of growth plate chondrocytes was restored in the bones of treated mice. Of interest in this regard, individuals afflicted with the inherited disorders associated with FGFR aberrations, such as dwarfism, do not have an increased incidence of cancer, despite having mutations that are often identical to those somatic FGFR aberrations that characterize certain tumors. The secondary modulatory influences that mitigate the risk of cancer in these individuals are of interest. Whether or not treating them at an early age with FGFR inhibitors would increase the later risk of cancer if the inhibitors were withdrawn would need to be considered.

In summary, perturbations in the FGF/FGFR machinery appear to underlie a variety of inherited syndromes, as well as benign and malignant disorders. The advent of potent FGFR inhibitors provides important new agents in the armamentarium against diseases caused by FGF/FGFR abnormalities.

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    Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annual review of biochemistry. 2000;69:373-398.

    Not in our library10.1146/annurev.biochem.69.1.373

  22. 22.

    Kim I, Moon S-O, Yu K-H, Kim U-H, Koh GY. A novel fibroblast growth factor receptor-5 preferentially expressed in the pancreas. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 2001;1518(1–2):152-156.

    Not in our library10.1016/s0167-4781(00)00282-7

  23. 23.

    Sleeman M, Fraser J, McDonald M, Yuan S, White D, Grandison P, Murison JG. Identification of a new fibroblast growth factor receptor, FGFR5. Gene. 2001;271(2):171-182.

    Not in our library10.1016/s0378-1119(01)00518-2

  24. 24.

    Klint P, Claesson-Welsh L. Signal transduction by fibroblast growth factor receptors. Frontiers in bioscience: a journal and virtual library. 1999;4:D165-77.

    Not in our library10.2741/klint

  25. 25.

    Jin M, Du X, Chen L. Cross-talk between FGF and other cytokine signalling pathways during endochondral bone development. Cell biology international. 2012;36(8):691-696.

    Not in our library10.1042/cbi20110352

  26. 26.

    Horton, W. A. (2006). MOLECULAR PATHOGENESIS OF ACHONDROPLASIA. Growth Genet Horm.

    Not in our library

  27. 27.

    Katoh M. Cancer genomics and genetics of FGFR2 (Review). International journal of oncology. 2008;33(2):233-237.

    Not in our library

  28. 28.

    Olsen, S. K., Garbi, M., Zampieri, N., Eliseenkova, A. V., Ornitz, D. M., Goldfarb, M., & Mohammadi, M. (2003). Fibroblast Growth Factor (FGF) Homologous Factors Share Structural but Not Functional Homology with FGFs. Journal of Biological \ldots.

    Not in our library10.1074/jbc.m303183200

  29. 29.

    Itoh N, Ornitz DM. Functional evolutionary history of the mouse Fgf gene family. Developmental dynamics: an official publication of the American Association of Anatomists. 2008;237(1):18-27.

    Not in our library10.1002/dvdy.21388

  30. 30.

    Potthoff MJ, Kliewer SA, Mangelsdorf DJ. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes & development. 2012;26(4):312-324.

    Not in our library10.1101/gad.184788.111

  31. 31.

    Fukumoto S. Actions and mode of actions of FGF19 subfamily members. Endocrine journal. 2008;55(1):23-31.

    Not in our library10.1507/endocrj.kr07e-002

  32. 32.

    Guillemot F, Zimmer C. From cradle to grave: the multiple roles of fibroblast growth factors in neural development. Neuron. 2011;71(4):574-588.

    Not in our library10.1016/j.neuron.2011.08.002

  33. 33.

    Abuharbeid S, Czubayko F, Aigner A. The fibroblast growth factor-binding protein FGF-BP. The international journal of biochemistry & cell biology. 2006;38(9):1463-1468.

    Not in our library10.1016/j.biocel.2005.10.017

  34. 34.

    Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. The Journal of biological chemistry. 2006;281(23):15694-15700.

    Not in our library10.1074/jbc.m601252200

  35. 35.

    Ornitz DM, Xu J, Colvin JS, McEwen DG, MacArthur CA, Coulier F, Goldfarb M. Receptor specificity of the fibroblast growth factor family. The Journal of biological chemistry. 1996;271(25):15292-15297.

    Not in our library10.1074/jbc.271.25.15292

  36. 36.

    Itoh N. The Fgf families in humans, mice, and zebrafish: their evolutional processes and roles in development, metabolism, and disease. Biological & pharmaceutical bulletin. 2007;30(10):1819-1825.

    Not in our library10.1248/bpb.30.1819

  37. 37.

    Hehr U, Muenke M. Craniosynostosis syndromes: from genes to premature fusion of skull bones. Molecular genetics and metabolism. 1999;68(2):139-151.

    Not in our library10.1006/mgme.1999.2915

  38. 38.

    Wu DQ, Kan MK, Sato GH, Okamoto T, Sato JD. Characterization and molecular cloning of a putative binding protein for heparin-binding growth factors. The Journal of biological chemistry. 1991;266(25):16778-16785.

    Not in our library

  39. 39.

    Böttcher RT, Pollet N, Delius H, Niehrs C. The transmembrane protein XFLRT3 forms a complex with FGF receptors and promotes FGF signalling. Nature cell biology. 2004;6(1):38-44.

    Not in our library10.1038/ncb1082

  40. 40.

    Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nature reviews Drug discovery. 2009;8(3):235-253.

    Not in our library10.1038/nrd2792

  41. 41.

    Hacohen N, Kramer S, Sutherland D, Hiromi Y, Krasnow MA. sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell. 1998;92(2):253-263.

    Not in our library10.1016/s0092-8674(00)80919-8

  42. 42.

    Cabrita MA, Christofori G. Sprouty proteins, masterminds of receptor tyrosine kinase signaling. Angiogenesis. 2008;11(1):53-62.

    Not in our library10.1007/s10456-008-9089-1

  43. 43.

    Tsang, M., & Dawid, I. B. (2004). Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Science’s STKE: signal transduction knowledge environment, 2004(228), pe17.

    Not in our library10.1126/stke.2282004pe17

  44. 44.

    Steinberg F, Zhuang L, Beyeler M, Kälin RE, Mullis PE, Brändli AW, Trueb B. The FGFRL1 receptor is shed from cell membranes, binds fibroblast growth factors (FGFs), and antagonizes FGF signaling in Xenopus embryos. The Journal of biological chemistry. 2010;285(3):2193-2202.

    Not in our library10.1074/jbc.m109.058248

  45. 45.

    Trueb B. Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cellular and molecular life sciences: CMLS. 2011;68(6):951-964.

    Not in our library10.1007/s00018-010-0576-3

  46. 46.

    Rieckmann T, Zhuang L, Flück CE, Trueb B. Characterization of the first FGFRL1 mutation identified in a craniosynostosis patient. Biochimica et biophysica acta. 2009;1792(2):112-121.

    Not in our library10.1016/j.bbadis.2008.11.006

  47. 47.

    Schild C, Trueb B. Aberrant expression of FGFRL1, a novel FGF receptor, in ovarian tumors. International journal of molecular medicine. 2005;16(6):1169-1173.

    Not in our library

  48. 48.

    Garcia S, Dirat B, Tognacci T, Rochet N, Mouska X, Bonnafous S, Gouze E. Postnatal soluble FGFR3 therapy rescues achondroplasia symptoms and restores bone growth in mice. Science Translational Medicine. 2013;5(203):203ra-124.

    Not in our library10.1126/scitranslmed.3006247

  49. 49.

    Cohen MM. Neoplasms associated with alterations in fibroblast growth factor receptors. American journal of medical genetics Part A. 2003;119A(2):97-100.

    Not in our library10.1002/ajmg.a.10058

  50. 50.

    Andreou A, Lamy A, Layet V, Cailliez D, Gobet F, Pfister C, Frebourg T. Early-onset low-grade papillary carcinoma of the bladder associated with Apert syndrome and a germline FGFR2 mutation (Pro253Arg). American journal of medical genetics Part A. 2006;140(20):2245-2247.

    Not in our library10.1002/ajmg.a.31430

  51. 51.

    Rouzier C, Soler C, Hofman P, Brennetot C, Bieth E, Pedeutour F. Ovarian dysgerminoma and Apert syndrome. Pediatric blood & cancer. 2008;50(3):696-698.

    Not in our library10.1002/pbc.21156

  52. 52.

    Barbosa, M., Almeida, M. do R., Reis-Lima, M., Pinto-Basto, J., & dos Santos, H. G. (2009). Muenke syndrome with osteochondroma. American journal of medical genetics. Part A, 149A(2), 260–261.

    Not in our library10.1002/ajmg.a.32616

  53. 53.

    Bourdeaut F, Miquel C, Di Rocco F, Grison C, Richer W, Brugieres L, Collet C. Germline mutations in FGF receptors and medulloblastomas. American journal of medical genetics Part A. 2013;161A(2):382-385.

    Not in our library10.1002/ajmg.a.35719

  54. 54.

    Logié A, Dunois-Lardé C, Rosty C, Levrel O, Blanche M, Ribeiro A, Radvanyi F. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans. Human molecular genetics. 2005;14(9):1153-1160.

    Not in our library10.1093/hmg/ddi127

  55. 55.

    Hafner C, van Oers JMM, Vogt T, Landthaler M, Stoehr R, Blaszyk H, Hartmann A. Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi. Journal of Clinical Investigation. 2006;116(8):2201-2207.

    Not in our library10.1172/jci28163

  56. 56.

    cbioportal. (n.d.). Retrieved from http://www.cbioportal.org/public-portal/index.do.

    Not in our library

  57. 57.

    Hattori Y, Itoh H, Uchino S, Hosokawa K, Ochiai A, Ino Y, Terada M. Immunohistochemical detection of K-sam protein in stomach cancer. Clinical cancer research: an official journal of the American Association for Cancer Research. 1996;2(8):1373-1381.

    Not in our library

  58. 58.

    Gust KM, McConkey DJ, Awrey S, Hegarty PK, Qing J, Bondaruk J, Black PC. Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer. Molecular Cancer Therapeutics. 2013;12(7):1245-1254.

    Not in our library10.1158/1535-7163.mct-12-1150

  59. 59.

    Gartside MG, Chen H, Ibrahimi OA, Byron SA, Curtis AV, Wellens CL, Pollock PM. Loss-of-function fibroblast growth factor receptor-2 mutations in melanoma. Molecular cancer research: MCR. 2009;7(1):41-54.

    Not in our library10.1158/1541-7786.mcr-08-0021

  60. 60.

    Heist RS, Mino-Kenudson M, Sequist LV, Tammireddy S, Morrissey L, Christiani DC, Iafrate AJ. FGFR1 Amplification in Squamous Cell Carcinoma of The Lung. Journal of Thoracic Oncology. 2012;7(12):1775-1780.

    Not in our library10.1097/jto.0b013e31826aed28

  61. 61.

    Weiss J, Sos ML, Seidel D, Peifer M. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Science translational medicine. 2010;2(62):62ra93.

    Not in our library10.1126/scitranslmed.3001451

  62. 62.

    Albiges, L., Quidville, V., Valent, A., Mathieu, M. C., Drusch, F., Koscielny, S., … Andre, F. (2009). FGFR1 amplification and FGF gain in breast cancer. In San Antonio Breast Cancer Symposium. Institut Gustave Roussy, villejuif, France.

    Not in our library

  63. 63.

    Jackson CC, Medeiros LJ, Miranda RN. 8p11 myeloproliferative syndrome: a review. Human Pathology. 2010;41(4):461-476.

    Not in our library10.1016/j.humpath.2009.11.003

  64. 64.

    Liu J, Guzman MA, Pezanowski D, Patel D, Hauptman J, Keisling M, de Chadarévian J-P. FOXO1-FGFR1 fusion and amplification in a solid variant of alveolar rhabdomyosarcoma. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 2011;24(10):1327-1335.

    Not in our library10.1038/modpathol.2011.98

  65. 65.

    Grand EK, Chase AJ, Heath C, Rahemtulla A, Cross NCP. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia. 2004;18(5):962-966.

    Not in our library10.1038/sj.leu.2403347

  66. 66.

    Yagasaki F, Wakao D, Yokoyama Y, Uchida Y, Murohashi I, Kayano H, Bessho M. Fusion of ETV6 to fibroblast growth factor receptor 3 in peripheral T-cell lymphoma with a t(4;12)(p16;p13) chromosomal translocation. Cancer Research. 2001;61(23):8371-8374.

    Not in our library

  67. 67.

    Katoh M, Katoh M. Recombination cluster around FGFR2-WDR11-HTPAPL locus on human chromosome 10q26. International Journal of Molecular Medicine. 2003;11(5):579-583.

    Not in our library

  68. 68.

    Singh D, Chan JM, Zoppoli P, Niola F, Sullivan R, Castano A, Iavarone A. Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma. Science. 2012;337(6099):1231-1235.

    Not in our library10.1126/science.1220834

  69. 69.

    Soria J-C, DeBraud F, Bahleda R, Adamo B, Andre F, Dientsmann R, Tabernero J. Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 2014;25(11):2244-2251.

    Not in our library10.1093/annonc/mdu390

  70. 70.

    Nakanishi Y, Akiyama N, Tsukaguchi T, Fujii T, Sakata K, Sase H, Ishii N. The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor. Molecular Cancer Therapeutics. 2014;13(11):2547-2558.

    Not in our library10.1158/1535-7163.mct-14-0248

  71. 71.

    Bellovin DI, Palencia S, Hestir K, Lee E, DeYoung MP, Brennan T, Baker K. Abstract 5449: FP-1039/GSK3052230, an FGF ligand trap, enhances VEGF antagonist therapy in preclinical models of RCC and HCC. Cancer Research. 2014;74(19 Supplement):5449-5449.

    Not in our library10.1158/1538-7445.am2014-5449

  72. 72.

    Sohl CD, Ryan MR, Luo B, Frey KM, Anderson KS. Illuminating the Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance for the FGFR1 Gatekeeper Mutation: The Achilles’ Heel of Targeted Therapy. ACS chemical biology. 2015.

    Not in our library10.1021/acschembio.5b00014

  73. 73.

    Chell V, Balmanno K, Little AS, Wilson M, Andrews S, Blockley L, Cook SJ. Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance. Oncogene. 2013;32(25):3059-3070.

    Not in our library10.1038/onc.2012.319

  74. 74.
    The N550K/H Mutations in FGFR2 Confer Differential Resistance to PD173074, Dovitinib, and Ponatinib ATP-Competitive Inhibitors · 2013
    Not checked
  75. 75.

    Crystal AS, Shaw AT, Sequist LV, Friboulet L, Niederst MJ, Lockerman EL, Engelman JA. Patient-derived models of acquired resistance can identify effective drug combinations for cancer. Science. 2014;346(6216):1480-1486.

    Not in our library10.1126/science.1254721

  76. 76.

    Harbinski F, Craig VJ, Sanghavi S, Jeffery D, Liu L, Sheppard KA, Tiedt R. Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth. Cancer Discovery. 2012;2(10):948-959.

    Not in our library10.1158/2159-8290.cd-12-0237

  77. 77.

    Javidi-Sharifi N, Traer E, Martinez J, Gupta A, Taguchi T, Dunlap J, Tyner JW. Crosstalk between KIT and FGFR3 Promotes Gastrointestinal Stromal Tumor Cell Growth and Drug Resistance. Cancer Research. 2015;75(5):880-891.

    Not in our library10.1158/0008-5472.can-14-0573

  78. 78.

    Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Ashworth A. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer research. 2010;70(5):2085-2094.

    Not in our library10.1158/0008-5472.can-09-3746

  79. 79.

    Schwaederlé, M., Daniels, G. A., Piccioni, D. E., Fanta, P. T., Schwab, R. B., Shimabukuro, K. A., … Kurzrock, R. (2014). Cyclin alterations in diverse cancers: Outcome and co-amplification network. Oncotarget.

    Not in our library10.18632/oncotarget.2848

  80. 80.

    Wheler, J. J., Parker, B. A., Lee, J. J., Atkins, J. T., Janku, F., Tsimberidou, A. M., … Kurzrock, R. (2014). Unique molecular signatures as a hallmark of patients with metastatic breast cancer: Implications for current treatment paradigms. Oncotarget.

    Not in our library10.18632/oncotarget.1946

  81. 81.

    Schwaederle M, Parker BA, Schwab RB, Fanta PT, Boles SG, Daniels GA, Kurzrock R. Molecular tumor board: the University of California-San Diego Moores Cancer Center experience. The Oncologist. 2014;19(6):631-636.

    Not in our library10.1634/theoncologist.2013-0405

  82. 82.

    Tsimberidou A-M, Iskander NG, Hong DS, Wheler JJ, Falchook GS, Fu S, Kurzrock R. Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative. Clinical cancer research: an official journal of the American Association for Cancer Research. 2012;18(22):6373-6383.

    Not in our library10.1158/1078-0432.ccr-12-1627

  83. 83.

    omim.org. (n.d.). Retrieved from http://www.omim.org/.

    Not in our library

  84. 84.

    Cohen MM. Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. American journal of medical genetics. 1993;45(3):300-307.

    Not in our library10.1002/ajmg.1320450305

  85. 85.

    Vogels A, Fryns J-P. Pfeiffer syndrome. Orphanet journal of rare diseases. 2006;1:19.

    Not in our library10.1186/1750-1172-1-19

  86. 86.

    Ibrahimi OA, Zhang F, Eliseenkova AV, Linhardt RJ, Mohammadi M. Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. Human Molecular Genetics. 2004;13(1):69-78.

    Not in our library10.1093/hmg/ddh011

  87. 87.

    Davies, H., Hunter, C., Smith, R., Stephens, P., Greenman, C., Bignell, G., … Futreal, P. A. (2005). Somatic Mutations of the Protein Kinase Gene Family in Human Lung Cancer.

    Not in our library10.1158/0008-5472.can-05-1855

  88. 88.

    Ruhe, J. E., Streit, S., Hart, S., Wong, C.-H., Specht, K., Knyazev, P., … Ullrich, A. (2007). Genetic Alterations in the Tyrosine Kinase Transcriptome of Human Cancer Cell Lines. Cancer Research.

    Not in our library10.1158/0008-5472.can-07-2703

  89. 89.

    White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, Econs MJ. Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. American journal of human genetics. 2005;76(2):361-367.

    Not in our library10.1086/427956

  90. 90.

    Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, White KE, Gehron Robey P. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. Journal of Clinical Investigation. 2003;112(5):683-692.

    Not in our library10.1172/jci18399

  91. 91.

    Moloney DM, Slaney SF, Oldridge M, Wall SA, Sahlin P, Stenman G, Wilkie AO. Exclusive paternal origin of new mutations in Apert syndrome. Nature genetics. 1996;13(1):48-53.

    Not in our library10.1038/ng0596-48

  92. 92.

    Miraoui, H., Ringe, J., & Häupl, T. (2010). Increased EFG-and PDGFα-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. Human molecular \ldots.

    Not in our library10.1093/hmg/ddq045

  93. 93.

    Pollock PM, Gartside MG, Dejeza LC, Powell MA, Mallon MA, Davies H, Goodfellow PJ. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene. 2007;26(50):7158-7162.

    Not in our library10.1038/sj.onc.1210529

  94. 94.
    FGFR2 Point Mutations in 466 Endometrioid Endometrial Tumors: Relationship with MSI, KRAS, PIK3CA, CTNNB1 Mutations and Clinicopathological Features · 2012
    Corrected
  95. 95.

    Passos-Bueno MR, Wilcox WR, Jabs EW, Serti AL, Alonso LG, Kitoh H. Clinical spectrum of fibroblast growth factor receptor mutations. Human Mutation. 1999;14(2):115-125.

    Not in our library10.1002/(sici)1098-1004(1999)14:2<115::aid-humu3>3.0.co;2-2

  96. 96.

    Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, Malcolm S. Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nature genetics. 1994;8(1):98-103.

    Not in our library10.1038/ng0994-98

  97. 97.

    Glaser RL, Jiang W, Boyadjiev SA, Tran AK, Zachary AA, Van Maldergem L, Jabs EW. Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. American journal of human genetics. 2000;66(3):768-777.

    Not in our library10.1086/302831

  98. 98.

    Jang JH, Shin KH, Park JG. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Research. 2001;61(9):3541-3543.

    Not in our library

  99. 99.

    Chokdeemboon C, Mahatumarat C, Rojvachiranonda N, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V. FGFR1 and FGFR2 mutations in Pfeiffer syndrome. The Journal of craniofacial surgery. 2013;24(1):150-152.

    Not in our library10.1097/scs.0b013e3182646454

  100. 100.

    Cornejo-Roldan, L. R., Roessler, E., & Muenke, M. (1999). Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome - Springer. Human genetics.

    Not in our library10.1007/s004390050979

  101. 101.

    Chen L, Adar R, Yang X, Monsonego EO, Li C, Hauschka PV, Deng CX. Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. Journal of Clinical Investigation. 1999;104(11):1517-1525.

    Not in our library10.1172/jci6690

  102. 102.

    Monsonego-Ornan E, Adar R, Feferman T, Segev O, Yayon A. The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Molecular and cellular biology. 2000;20(2):516-522.

    Not in our library10.1128/mcb.20.2.516-522.2000

  103. 103.

    Henderson JE, Naski MC, Aarts MM, Wang D, Cheng L, Goltzman D, Ornitz DM. Expression of FGFR3 with the G380R Achondroplasia Mutation Inhibits Proliferation and Maturation of CFK2 Chondrocytic Cells. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2000;15(1):155-165.

    Not in our library10.1359/jbmr.2000.15.1.155

  104. 104.

    Knowles MA. Novel therapeutic targets in bladder cancer: mutation and expression of FGF receptors. Future oncology (London, England). 2008;4(1):71-83.

    Not in our library10.2217/14796694.4.1.71

  105. 105.

    Ahmad I, Iwata T, Leung HY. Mechanisms of FGFR-mediated carcinogenesis. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2012;1823(4):850-860.

    Not in our library10.1016/j.bbamcr.2012.01.004

  106. 106.

    Delezoide AL, Lasselin-Benoist C, Legeai-Mallet L, Brice P, Senée V, Yayon A, Bonaventure J. Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses. Human molecular genetics. 1997;6(11):1899-1906.

    Not in our library10.1093/hmg/6.11.1899

  107. 107.

    Wilcox WR, Tavormina PL, Krakow D, Kitoh H, Lachman RS, Wasmuth JJ, Rimoin DL. Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. American journal of medical genetics. 1998;78(3):274-281.

    Not in our library10.1002/(sici)1096-8628(19980707)78:3<274::aid-ajmg14>3.0.co;2-c

  108. 108.

    Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR. Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3 mutations. American journal of medical genetics. 1999;84(5):476-480.

    Not in our library10.1002/(sici)1096-8628(19990611)84:5<476::aid-ajmg12>3.0.co;2-x

  109. 109.

    Di Martino E, Tomlinson DC, Knowles MA. A Decade of FGF Receptor Research in Bladder Cancer: Past, Present, and Future Challenges. Advances in Urology. 2012;2012:e429213.

    Not in our library10.1155/2012/429213

  110. 110.

    Salgia R. Fibroblast growth factor signaling and inhibition in non-small cell lung cancer and their role in squamous cell tumors. Cancer Medicine. 2014;3(3):681-692.

    Not in our library10.1002/cam4.238

  111. 111.

    Liao RG, Jung J, Tchaicha J, Wilkerson MD, Sivachenko A, Beauchamp EM, Hammerman PS. Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma. Cancer Research. 2013;73(16):5195-5205.

    Not in our library10.1158/0008-5472.can-12-3950

  112. 112.

    Webster MK, D’Avis PY, Robertson SC, Donoghue DJ. Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Molecular and cellular biology. 1996;16(8):4081-4087.

    Not in our library10.1128/mcb.16.8.4081

  113. 113.

    Lievens PM-J, Liboi E. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. The Journal of biological chemistry. 2003;278(19):17344-17349.

    Not in our library10.1074/jbc.m212710200

  114. 114.

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    Bellus GA, Garber AT, Bryke CR, Weaver CA, Speiser PW, Webster MK, Spector EB. FGFR3 Mutations K650N and K650Q Cause Hypochondroplasia. Genetics in Medicine. 2000;2(1):76-76.

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    Heuertz S, Le Merrer M, Zabel B, Wright M, Legeai-Mallet L, Cormier-Daire V, Bonaventure J. Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia. European Journal of Human Genetics. 2006;14(12):1240-1247.

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    Abdel-Salam GMH, Flores-Sarnat L, El-Ruby MO, Parboosingh J, Bridge P, Eid MM, Temtamy SA. Muenke syndrome with pigmentary disorder and probable hemimegalencephaly: An expansion of the phenotype. American journal of medical genetics Part A. 2011;155A(1):207-214.

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    Brunello E, Brunelli M, Bogina G, Caliò A, Manfrin E, Nottegar A, Bonetti F. FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma. Journal of experimental & clinical cancer research: CR. 2012;31:103.

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    No notice
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    The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315-322.

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    Goke F, Franzen A, Roopika M, Schroeck A, Kirsten R, Boehm D, Perner S. In 25th European Congress of Pathology. 2013.

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    The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513(7517):202-209.

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    Xie, L., Su, X., Zhang, L., Yin, X., Tang, L., Zhang, X., … Ji, Q. (2013). FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clinical cancer research: an official journal of the American Association for Cancer Research.

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    FGFR2 gene amplification and clinicopathological features in gastric cancer · 2012
    No notice
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    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615.

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    Barretina J, Taylor BS, Banerji S, Ramos AH, Lagos-Quintana M, Decarolis PL, Singer S. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nature genetics. 2010;42(8):715-721.

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    Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat J-P, Chin L. A Landscape of Driver Mutations in Melanoma. Cell. 2012;150(2):251-263.

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    Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Levine DA. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73.

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    Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders. (2002)., Published online: 03 December 2002; | doi:10.1038/sj.ejhg.5200883, 10(12). doi:10.1038/sj.ejhg.5200883.

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    Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation · 2005
    Not checked
  137. 137.

    Taylor JG, Cheuk AT, Tsang PS, Chung J-Y, Song YK, Desai K, Khan J. Identification of FGFR4-activating mutations in human rhabdomyosarcomas that promote metastasis in xenotransplanted models. The Journal of Clinical Investigation. 2009;119(11):3395-3407.

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    Turkington RC, Longley DB, Allen WL, Stevenson L, McLaughlin K, Dunne PD, Johnston PG. Fibroblast growth factor receptor 4 (FGFR4): a targetable regulator of drug resistance in colorectal cancer. Cell Death & Disease. 2014;5(2):e1046.

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    Persson F, Winnes M, Andrén Y, Wedell B, Dahlenfors R, Asp J, Stenman G. High-resolution array CGH analysis of salivary gland tumors reveals fusion and amplification of the FGFR1 and PLAG1 genes in ring chromosomes. Oncogene. 2008;27(21):3072-3080.

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    Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, Shibata T. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology. 2014;59(4):1427-1434.

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    Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-525.

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  143. 143.

    Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Aparicio S. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395-399.

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    Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Meyerson M. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;486(7403):405-409.

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    Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, Stratton MR. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486(7403):400-404.

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    Not checked
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    Mountzios G, Rampias T, Psyrri A. The mutational spectrum of squamous-cell carcinoma of the head and neck: targetable genetic events and clinical impact. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 2014.

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  148. 148.

    The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543-550.

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    Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Meyerson M. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell. 2012;150(6):1107-1120.

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    Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Wilson RK. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455(7216):1069-1075.

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    Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Gerald WL. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11-22.

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    The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43-49.

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  153. 153.

    ancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330-337.

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  154. 154.

    McLendon R, Friedman A, Bigner D, Van Meir EG, Brat DJ, Mastrogianakis MG, Thomson E. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061-1068.

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    Ho AS, Kannan K, Roy DM, Morris LGT, Ganly I, Katabi N, Chan TA. The mutational landscape of adenoid cystic carcinoma. Nature genetics. 2013;45(7):791-798.

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    Brat DJ. Integrative Genomic Characterization of Lower Grade Gliomas. Neuro-Oncology. 2014;16:iii3.

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  157. 157.

    Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. The New England journal of medicine. 2013;368(22):2059-2074.

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  158. 158.

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  160. 160.

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  162. 162.

    Johnson PJ, Qin S, Park J-W, Poon RTP, Raoul J-L, Philip PA, Cheng A-L. Brivanib Versus Sorafenib As First-Line Therapy in Patients With Unresectable, Advanced Hepatocellular Carcinoma: Results From the Randomized Phase III BRISK-FL Study. Journal of Clinical Oncology, JCO. 2013;2012(48):4410.

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  163. 163.

    Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Tran E. Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma. Clinical Cancer Research. 2008;14(19):6146-6153.

    Not in our library10.1158/1078-0432.ccr-08-0509

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    Siu, L. L., Shapiro, J. D., Jonker, D. J., Karapetis, C. S., Zalcberg, J. R., Simes, J., … NCIC Clinical Trials Group and AGITG. (2012). Phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with metastatic (MET) chemotherapy refractory K-RAS wild-type (WT) colorectal carcinoma (CRC): The NCIC Clinical Trials Group and AGITG CO.20 trial. ASCO Meeting Abstracts, 30(4_suppl), 386.

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  165. 165.

    Meulenbeld HJ, Bleuse JP, Vinci EM, Raymond E, Vitali G, Santoro A, de Wit R. Randomized phase II study of danusertib in patients with metastatic castration-resistant prostate cancer after docetaxel failure. BJU international. 2013;111(1):44-52.

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  166. 166.

    Cohen RB, Jones SF, Aggarwal C, von Mehren M, Cheng J, Spigel DR, Burris HA. A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2009;15(21):6694-6701.

    Not in our library10.1158/1078-0432.ccr-09-1445

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    Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Escudier B. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. The Lancet. Oncology. 2014;15(3):286-296.

    Not in our library10.1016/s1470-2045(14)70030-0

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    Motzer, R. J., Porta, C., Bjarnason, G. A., Szcylik, C., Rha, S. Y., Esteban, E., … Escudier, B. J. (2012). Phase III trial of dovitinib (TKI258) versus sorafenib in patients with metastatic renal cell carcinoma after failure of anti-angiogenic (VEGF-targeted and mTOR inhibitor) therapies. ASCO Meeting Abstracts, 30(15_suppl), TPS4683.

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    Angevin, E., Lin, C., Pande, A. U., & Lopez, J. A. (2010). A phase I/II study of dovitinib (TKI258), a FGFR and VEGFR inhibitor, in patients (pts) with advanced or metastatic renal cell cancer: phase I results. ASCO Meeting \ldots.

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    Dienstmann R, Bahleda R, Adamo B, Rodon J, Varga A, Gazzah A, Soria J-C. Abstract CT325: First in human study of JNJ-42756493, a potent pan fibroblast growth factor receptor (FGFR) inhibitor in patients with advanced solid tumors. Cancer Research. 2014;74(19 Supplement):CT325-CT325.

    Not in our library10.1158/1538-7445.am2014-ct325

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    Schlumberger, M., Tahara, M., Wirth, L. J., Robinson, B., Brose, M. S., Elisei, R., … Sherman, S. I. (2014). A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT) [abstract]. In Journal of clinical oncology: official journal of the American Society of Clinical Oncology (p. LBA6008).

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  172. 172.
    Antitumor Activity of Lenvatinib (E7080): An Angiogenesis Inhibitor That Targets Multiple Receptor Tyrosine Kinases in Preclinical Human Thyroid Cancer Models · 2014
    No notice
  173. 173.

    Andre, F., Daly, F., Azim, H. A., Agrapart, V., Goulioti, T., Pinto, A. C. D. C. P., … Cortes, J. (2014). FINESSE: An open, three-cohort, phase II trial testing oral administration of lucitanib in patients with FGFR1-amplified or nonamplified estrogen receptor-positive metastatic breast cancer. Journal of Clinical Oncology, 32:5s(suppl; abstr TPS1134). Retrieved from http://meetinglibrary.asco.org/content/126911-144.

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    Bello E, Taraboletti G, Colella G, Zucchetti M, Forestieri D, Licandro SA, Damia G. The Tyrosine Kinase Inhibitor E-3810 Combined with Paclitaxel Inhibits the Growth of Advanced-Stage Triple-Negative Breast Cancer Xenografts. Molecular Cancer Therapeutics. 2013;12(2):131-140.

    Not in our library10.1158/1535-7163.mct-12-0275-t

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    Bello E, Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, Camboni G. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Research. 2011;71(4):1396-1405.

    Not in our library10.1158/0008-5472.can-10-2700

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    Carter, E. P., Fearon, A. E., & Grose, R. P. (n.d.). Careless talk costs lives: fibroblast growth factor receptor signalling and the consequences of pathway malfunction. Trends in Cell Biology. doi:10.1016/j.tcb.2014.11.003.

    Not in our library10.1016/j.tcb.2014.11.003

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    Pan B-S, Chan GKY, Chenard M, Chi A, Davis LJ, Deshmukh SV, Dinsmore CJ. MK-2461, a novel multitargeted kinase inhibitor, preferentially inhibits the activated c-Met receptor. Cancer Research. 2010;70(4):1524-1533.

    Not in our library10.1158/0008-5472.can-09-2541

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    Hanna, N. H., Kaiser, R., Sullivan, R. N., Aren, O. R., Ahn, M.-J., Tiangco, B., … Kim, J. H. (2013). Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. ASCO Meeting Abstracts, 31(15_suppl), 8034.

    Not in our library

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    Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Collard HR. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. New England Journal of Medicine. 2014;370(22):2071-2082.

    Not in our library10.1056/nejmoa1402584

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    Kristensen, G., Harter, P., Trédan, O., Sailer, M. O., Bamias, A., Colombo, N., … Bois, A. D. (2014). Independent review of AGO-OVAR 12, a GCIG/ENGOT-Intergroup phase III trial of nintedanib (N) in first-line therapy for ovarian cancer (OC). Journal of Clinical Oncology, 32:5s(suppl; abstr 5556^). Retrieved from http://meetinglibrary.asco.org/content/130341-144.

    Not in our library

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    Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Graus Porta D. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. Journal of Medicinal Chemistry. 2011;54(20):7066-7083.

    Not in our library10.1021/jm2006222

  182. 182.

    Guagnano V, Kauffmann A, Wöhrle S, Stamm C, Ito M, Barys L, Graus-Porta D. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discovery. 2012;2(12):1118-1133.

    Not in our library10.1158/2159-8290.cd-12-0210

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    Konecny, G. E., Kolarova, T., O’Brien, N. A., Winterhoff, B., Yang, G., Qi, J., … Slamon, D. J. (2013). Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells. Molecular Cancer Therapeutics.

    Not in our library10.1158/1535-7163.mct-12-0999

  184. 184.

    Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. The New England Journal of Medicine. 2014;370(18):1769-1770.

    Not in our library10.1056/nejmc1400731

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    Kasper B, Sleijfer S, Litière S, Marreaud S, Verweij J, Hodge RA, van der Graaf WTA. Long-term responders and survivors on pazopanib for advanced soft tissue sarcomas: subanalysis of two European Organisation for Research and Treatment of Cancer (EORTC) clinical trials 62043 and 62072. Annals of oncology: official journal of the European Society for Medical Oncology / ESMO. 2014;25(3):719-724.

    Not in our library10.1093/annonc/mdt586

  186. 186.

    O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Clackson T. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16(5):401-412.

    Not in our library10.1016/j.ccr.2009.09.028

  187. 187.

    Cortes JE, Kim D-W, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Investigators PACE. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. The New England Journal of Medicine. 2013;369(19):1783-1796.

    Not in our library10.1056/nejmoa1306494

  188. 188.

    Demetri GD, Reichardt P, Kang Y-K, Blay J-Y, Rutkowski P, Gelderblom H, GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295-302.

    Not in our library10.1016/s0140-6736(12)61857-1

  189. 189.

    Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.

    Not in our library10.1016/s0140-6736(12)61900-x

  190. 190.

    Ochiiwa H, Fujita H, Itoh K, Sootome H, Hashimoto A, Fujioka Y, Utsugi T. Abstract A270: TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities. Molecular Cancer Therapeutics. 2013;12(11 Supplement):A270-A270.

    Not in our library10.1158/1535-7163.targ-13-a270

  191. 191.

    Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocrine-Related Cancer. 2000;7(3):165-197.

    Not in our library10.1677/erc.0.0070165

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    Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends in Genetics. 2004;20(11):563-569.

    Not in our library10.1016/j.tig.2004.08.007

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