Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models

French, Dorothy; Lin, Benjamin C.; Wang, Manping; Adams, Camellia; Shek, Theresa; Hötzel, Kathy; Bolon, Brad; Ferrando, Ronald E.; Blackmore, C. A.; Schroeder, Kurt; Rodríguez, Luis A.; Hristopoulos, Maria; Venook, Rayna; Ashkenazi, Avi; Desnoyers, Luc

doi:10.1371/journal.pone.0036713

Cited by 186 publications

(178 citation statements)

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“…In this article, we show that one such variant, M70, fully retains the biologic activity of FGF19 in regulating bile acid homeostasis while devoid of tumorigenicity. Notably, we found that M70 binds to and activates FGFR4, which is assumed to mediate FGF19-associated tumorigenicity (13,16). Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity completely eliminated by M70.…”

Section: Introductionmentioning

confidence: 63%

“…Transgenic mice with ectopic expression of FGF19 in skeletal muscle develop HCC at the age of 10-to 12-month-old (11). This tumorigenic activity is thought to be mediated by the liver-enriched FGFR4, because inactivation of FGFR4 via gene knockout or by a neutralizing antibody reduces tumor burden in FGF19 transgenic mice (12,13). Therefore, targeting the FGF19-FGFR4 pathway has the potential for treating HCC.…”

Section: Introductionmentioning

confidence: 99%

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Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

et al. 2014

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Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. Although it is well established that FGF19 acts through the receptor complex FGFR4-b-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 (M70) that fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumorpromoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer. Cancer Res; 74(12); 3306-16. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

et al. 2014

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“…Both inhibitors exhibited excellent potency against typical cancer cell lines harboring FGFR amplifications or mutations, including the FGFR4-dependent cell line A2780, which is resistant to many current FGFR inhibitors. FGFR4 has been reported to play a very important role in metastasis, drug resistance, and poor prognosis (23,(68)(69)(70); therefore FIIN-2 and FIIN-3, with good FGFR4 potency, show promising potential for application in many FGFR-dependent cancer types such as breast cancer (63,71) and hepatocellular carcinoma (72,73). In addition, they are capable of overcoming the valine-to-methionine gatekeeper mutation in H2077 and H1581 cell lines, although similar mutations found in patients' specimens have been demonstrated experimentally to confer resistance to the leading clinical FGFR inhibitors (19,48,50).…”

Section: Discussionmentioning

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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“…Several different mAb have been developed to target components of the FGF-FGFR axis: GP369 (Bai et al, 2010), GAL-FR21 (Zhao et al, 2010), GAL-FR22 (Inokuchi et al, 2015), GAL-F2 , MFGR1877S (Fauvel and Yasri, 2014), hLD1.vb (Bumbaca et al, 2011), FP-1039(Marshall et al, 2011, R3Mab (French et al, 2012), PRO-001 (French et al, 2012), 1A6 (Pai et al, 2008) and LD1 (French et al, 2012). Two main mechanisms of action have been considered; either blocking ligand binding (trap-ligand) or preventing receptor dimerization.…”

Section: Antibodies Against Fgfs and Fgfrs And Fgf-ligand Trapmentioning

confidence: 99%

FGFR a promising druggable target in cancer: Molecular biology and new drugs

Porta

Borea²,

Coelho³

et al. 2017

Critical Reviews in Oncology/Hematology

179

162

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Introduction The Fibroblast Growth Factor Receptor (FGFR) family consists of Tyrosine Kinase Receptors (TKR) involved in several biological functions. Recently, alterations of FGFR have been reported to be important for progression and development of several cancers. In this setting, different studies are trying to evaluate the efficacy of different therapies targeting FGFR. Areas Covered This review summarizes the current status of treatments targeting FGFR, focusing on the trials that are evaluating the FGFR profile as inclusion criteria: Multi-Target, Pan-FGFR Inhibitors and anti-FGF (Fibroblast Growth Factor)/FGFR Monoclonal Antibodies. Expert opinion Most of the TKR share intracellular signaling pathways; therefore, cancer cells tend to overcome the inhibition of one tyrosine kinase receptor by activating another. The future of TKI (Tyrosine Kinase Inhibitor) therapy will potentially come from multi-targeted TKIs that target different TKR simultaneously. It is crucial to understand the interaction of the FGF-FGFR axis with other known driver TKRs. Based on this, it is possible to develop therapeutic strategies targeting multiple connected TKRs at once. One correct step in this direction is the reassessment of multi target inhibitors considering the FGFR status of the tumor. Another opportunity arises from assessing the use of FGFR TKI on patients harboring FGFR alterations

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Targeting FGFR4 Inhibits Hepatocellular Carcinoma in Preclinical Mouse Models

Cited by 186 publications

References 31 publications

Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

Separating Tumorigenicity from Bile Acid Regulatory Activity for Endocrine Hormone FGF19

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

FGFR a promising druggable target in cancer: Molecular biology and new drugs

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