Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer

Cole, Claire L.; Lau, Sin C; Backen, Alison; Clamp, Andrew R.; Rushton, Graham; Dive, Caroline; Hodgkinson, Cassandra L.; McVey, Rhona J; Kitchener, Henry C; Jayson, Gordon C

doi:10.4161/cbt.10.5.12585

Cited by 76 publications

(63 citation statements)

References 19 publications

(23 reference statements)

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“…More recently, an FGFR1-FGF2 autocrine pathway has been identified as a novel pathway of acquired resistance to EGFR-specific TKIs in NSCLC cell lines bearing activating mutations in EGFR (27). FGFR1 has also been involved in resistance to nontargeted chemotherapies as cytosine arabinoside in leukemia (28) or cisplatin in ovarian cancer and, in this case, the resistance of the SKOV3 cell line to this drug is also reversed by silencing this receptor (29). Other growth factor receptors as EGFR (3), HGF/Met (30), or IGF1 (31) have already been involved in tumor cell radioresistance and inhibitors of these pathways have been evaluated through clinical trials in association with radiotherapy (for review, ref.…”

Section: Discussionmentioning

confidence: 99%

FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway

et al. 2016

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FGF2 signaling in glioblastoma induces resistance to radiotherapy, so targeting FGF2/FGFR pathways might offer a rational strategy for tumor radiosensitization. To investigate this possibility, we evaluated a specific role for FGFR1 in glioblastoma radioresistance as modeled by U87 and LN18 glioblastomas in mouse xenograft models. Silencing FGFR1 decreased radioresistance in a manner associated with radiation-induced centrosome overduplication and mitotic cell death. Inhibiting PLCg (PLCG1), a downstream effector signaling molecule for FGFR1, was sufficient to produce similar effects, arguing that PLCg is an essential mediator of FGFR1-induced radioresistance. FGFR1 silencing also reduced expression of HIF1a, which in addition to its roles in hypoxic responses exerts an independent effect on radioresistance. Finally, FGFR1 silencing delayed the growth of irradiated tumor xenografts, in a manner that was associated with reduced HIF1a levels but not blood vessel alterations. Taken together, our results offer a preclinical proof of concept that FGFR1 targeting can degrade radioresistance in glioblastoma, a widespread problem in this tumor, prompting clinical investigations of the use of FGFR1 inhibitors for radiosensitization. Cancer Res; 76(10); 3036-44. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway

et al. 2016

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“…In colorectal cancer, FGFR2 is highly expressed and correlates with tumor growth, metastasis and angiogenesis (34). A reduction in FGFR2 expression was observed to inhibit proliferation of ovarian cancer cell lines in vitro and additionally reduced the half maximal inhibitory concentration of cisplatin (35). FGFR2 has been implicated in the regulation of apoptosis in several types of cancer.…”

Section: Discussionmentioning

confidence: 99%

miR-494 inhibits ovarian cancer cell proliferation and promotes apoptosis by targeting FGFR2

et al. 2016

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Abstract. MicroRNAs (miRs) have been reported to be key regulators in numerous types of cancer. The aim of the present study was to investigate the role of miR-494 in ovarian cancer. Expression of miR-494 was analyzed in ovarian cancer tissues and cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). miR-494 mimic or negative control was transiently transfected into A2780 and SKOV3 cell lines. A cell counting kit-8 assay was performed to assess the effects of miR-494 on cell proliferation, and flow cytometry was used to evaluate the apoptotic rate. The target gene of miR-494 was detected by luciferase assay. Expression of fibroblast growth factor receptor 2 (FGFR2) was identified using RT-qPCR and western blotting. In the present study, decreased expression of miR-494 was observed in ovarian cancer samples and cell lines. Overexpression of miR-494 inhibited ovarian cancer cell proliferation by inducing apoptosis. Additional investigation indicated that FGFR2 was a direct target of miR-494. Taken together, the results of the present study suggested that miR-494 suppressed ovarian cancer cell proliferation by inducing apoptosis via targeting FGFR2.

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“…Both EGFR and FGFR have been reported to be overexpressed and likely contributors in ovarian cancer (36,64,65), and FGF3/EGFR cooverexpression also was reported in NSCLC (77). In addition, the activation of FGFR autocrine pathways were found to be individually responsible for acquired resistance to gefitinib (an EGFR inhibitor) in NSCLC, and combination treatments such as PD173074 and gefitinib were required to restore effective growth inhibition (78,79).…”

Section: Discussionmentioning

confidence: 99%

“…To validate the dual inhibitory activity of FIIN-3, we picked the SKOV-3 ovarian carcinoma cell line, which is reported to overexpress both EGFR and FGFR and whose proliferation could be inhibited only partially by selective FGFR or EGFR inhibitors (36,64,65). SKOV-3 cells were treated with FIIN-2, FIIN-3, and BGJ398 in the presence or absence of FGF or EGF ligands, and the growth response was assessed.…”

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.

169

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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Inhibition of FGFR2 and FGFR1 increases cisplatin sensitivity in ovarian cancer

Cited by 76 publications

References 19 publications

FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway

FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway

miR-494 inhibits ovarian cancer cell proliferation and promotes apoptosis by targeting FGFR2

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

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