Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma

Cheng, Ann‐Lii; Shen, Ying‐Chun; Zhu, Andrew X.

doi:10.1159/000335472

Cited by 49 publications

(40 citation statements)

References 88 publications

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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.

165

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: 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.

165

132

View full text Add to dashboard Cite

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“…Another study reported that FGFR2 overexpression in HCC tumors was associated with a high Ki-67 proliferation index and high levels of serum alpha-fetoprotein, and was linked to the development of multiple sites of metastasis (19). In addition, overexpression of FGFR3 has been associated with a higher grade and poorer differentiation status in HCC tumors, suggesting that increased FGFR3 expression may contribute to advanced HCC tumorigenesis (20). Thus, FGFRs may act as potent regulators in a variety of cancers.…”

Section: Introductionmentioning

confidence: 99%

Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity

Choi

Shin

et al. 2015

Molecular Cancer Therapeutics

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The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF-MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET. Mol Cancer Ther; 14(11); 2613-22. Ó2015 AACR.

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“…Aberrations of FGF/FGFR signaling have been reported to be involved in the tumorigenesis [22] and Table 5 Association of rs7825208 genotypes and tumor characteristics in HCC patients angiogenesis [23] of advanced HCC. Among the four FGFRs, the role of FGFR4 has been most extensively studied.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of FGFR1 in HBV-related hepatocellular carcinoma

et al. 2015

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Hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in China. It is important to understand the genetic mechanisms underlying the development and progression of HBV-related HCC and to identify new biomarkers for clinical treatment. The important role of fibroblast growth factor receptors (FGFRs) has been widely recognized in many types of cancers, but the association between FGFR polymorphisms and HCC carcinogenesis has been rarely reported. In this study, 199 patients with HBV-associated cirrhosis, 203 with HBV-associated HCC, and 184 healthy controls with no liver diseases were enrolled as participants. Using SNaPshot assays, five SNPs (rs13317, rs7825208, rs1047057, rs1047111, and rs1966265) of growth factor receptor genes were genotyped. Our results showed that the G/A and G/G genotypes at rs7825208 of FGFR1 were negatively correlated with HBV-related HCC (odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.22-0.93, P = 0.027). However, after Bonferroni correction, these significant differences no longer existed (P > 0.05). Our results indicated that these five polymorphisms of fibroblast growth factor receptor genes do not play any independent roles in the tumorigenesis and progression of HBV-related HCC in Han Chinese patients.

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Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma

Cited by 49 publications

References 88 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

Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity

Polymorphisms of FGFR1 in HBV-related hepatocellular carcinoma

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