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Ref Type Journal Article
PMID (26351320)
Authors Jo JC, Choi EK, Shin JS, Moon JH, Hong SW, Lee HR, Kim SM, Jung SA, Lee DH, Jung SH, Lee SH, Kim JE, Kim KP, Hong YS, Suh YA, Jang SJ, Lee JS, Jin DH, Kim TW
Title Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity.
Journal Molecular cancer therapeutics
Vol 14
Issue 11
Date 2015 Nov
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 pos FGFR2 pos hepatocellular carcinoma no benefit PHA-665752 Preclinical - Cell culture Actionable In a preclinical study, PHA-665752 treatment did not result in decreased colony formation or reduced phosphorylation levels of FGFR1 and FGFR2 in hepatocellular carcinoma cells in culture (PMID: 26351320). 26351320
FGFR1 pos FGFR2 pos hepatocellular carcinoma sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, hepatocellular carcinoma cell lines treated with AZD4547 demonstrated decreased phosphorylation of FGFR1 and FGFR2, reduced colony formation, and evidence of apoptotic activity in culture (PMID: 26351320). 26351320