간암 세포주에서 fibroblast growth factor receptor 억제를 통하여 MET 억제제에 대한 내성극복 : Inhibition of fibroblast growth factor receptor can overcome the resistance to MET inhibitor in human hepatocellular carcinoma
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The MET receptor tyrosine kinase, which is the receptor for hepatocyte growth factor (HGF), is implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad spectrum of human cancers, including hepatocellular carcinoma (HCC). HCC patients with an active HGF/MET signaling pathway have a worse prognosis. Recently, MET was suggested as a potential target for HCC with an active HGF/MET signaling pathway. However, the resistant mechanisms required for effective treatment of MET inhibitors remain to be elucidated. Here, we show that HCC cells display different sensitivities to MET inhibitor, PHA665752, by the status of phosphorylation of fibroblast growth factor receptor (FGFR). Treatment of cells expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce growth inhibition and cell death, whereas treatment with AZD4547, pan-FGFR inhibitor, resulted in the decreased colony formation and the cleavage of caspase-3. Knockdown of endogenous FGFR1 or 2 via RNA interference in HCC cells expressing phospho-FGFR1 or 2 and phospho-MET overcame resistance to PHA665752 treatment. Moreover, in the double knockdown of FGFR1 and 2, dual inhibition of FGFR1 and 2 showed the additive effect to overcome the resistance to PHA665752. Consistently, treatment of primary cancer cells from HCC patient expressing both phospho-FGFR1 or 2 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 activation of downstream effectors of cell growth, proliferation, and survival. Based on our findings, we conclude that FGFR pathway is critical for HCC survival, and targeting its signaling by AZD4547 may be beneficial in the treatment of HCC expressing phospho-FGFR1 or 2 and phospho-MET.