Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	11	2015 Nov	2613-22	Mol Cancer Ther

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	Fexagratinib	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