Overexpression of fibroblast growth factor receptors FGFR1 and FGFR2 in renal cell carcinoma

Tsimafeyeu, Ilya; Демидов, Лев В.; Степанова, Е. В.; Wynn, Nigel; Ta, Hung

doi:10.3109/00365599.2011.552436

Cited by 48 publications

(24 citation statements)

References 15 publications

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“…Translocation events implicating the FGFR1 gene and various fusions of FGFR1 are found in myeloproliferative syndromes (12); chromosomal translocations of FGFR1 or FGFR3 and the transforming acidic coiled-coil genes (TACC1 or TACC3) are oncogenic in glioblastoma multiforme, bladder cancer, head and neck cancer, and lung cancer (13)(14)(15)(16); oncogenic mutations of FGFR2 and FGFR3 are observed in lung squamous cell carcinoma; FGFR2 N549K is observed in 25% of endometrial cancers; FGFR3 t(4;14) alterations are reported in 15-20% of multiple myeloma (17)(18)(19); FGFR4 Y367C mutation in the transmembrane domain drives constitutive activation and enhanced tumorigenic phenotypes in a breast carcinoma cell line (20)(21)(22); and K535 and E550 mutants are reported to activate FGFR4 in rhabdomyosarcoma (23). FGFR amplification is reported in various cancers (24,25): FGFR1 is amplified in colorectal, lung, and renal cell cancers (26,27); FGFR2 is amplified in gastric cancer and colorectal cancer (28,29); FGFR3 is commonly amplified in bladder cancer and also is reported for cervical, oral, and hematological cancers (30)(31)(32); and FGFR4 is amplified in hepatocellular carcinoma, gastric cancer, pancreatic cancer, and ovarian cancer (33)(34)(35)(36)(37). FGFR also is involved in autocrine activation of STAT3 as a positive feedback in many drug-treated cancer cells which are driven by diverse oncogenes such as EGFR, ALK, MET, and KRAS (38).…”

Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

132

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The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

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Section: Significancementioning

confidence: 99%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

164

132

View full text Add to dashboard Cite

show abstract

“…Other than this, overexpression of FGFR1 and FGFR2 has been reported in renal cell carcinoma [110]. FGFR2 is overexpressed in breast cancer and gastric cancer [111,112]. Human myeloid cells, bladder carcinoma as well as urinary tract carcinomas overexpress FGFR3 [113][114][115].…”

Section: Fgf and Fgfrs: Roles In Cancermentioning

confidence: 99%

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

Khalid¹,

Javaid²

2016

J Cancer Sci Ther

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“…The level of FGFR expression was compared with 40 specimens of normal human kidney tissue (selected from the surgical diagnostic files) [15]. FGFR1 expression was identified in 98% of the cases in primary renal tumor cells and in 82.5% of the cases in lymph node metastases.…”

Section: Importance Of the Fgf/fgfr Pathway In Rcc Pathogenesismentioning

confidence: 99%

Fibroblast Growth Factor Receptor 1 as a Target for the Therapy of Renal Cell Carcinoma

Tsimafeyeu

Bratslavsky

2015

Oncology

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Dysregulation of fibroblast growth factor (FGF) signaling in renal cell carcinoma is now well understood, and it is becoming increasingly likely that certain tumors become dependent on an activation of this pathway for their growth and survival. Dissecting the FGF/FGF receptor (FGFR) pathway offers the hope of developing new therapeutic approaches that selectively target the FGF/FGFR axis in patients whose tumors are known to harbor FGF/FGFR dysregulation. In this review, we summarize the existing data on the role of FGFR1 in the pathogenesis of renal cell carcinoma and discuss methodological issues for drug investigation in this setting.

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Overexpression of fibroblast growth factor receptors FGFR1 and FGFR2 in renal cell carcinoma

Abstract: This study has shown for the first time that FGFR1 is highly expressed in RCC patients.

Cited by 48 publications

References 15 publications

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

Fibroblast Growth Factor Receptor 1 as a Target for the Therapy of Renal Cell Carcinoma

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