Hepatocyte growth factor reduces sensitivity to the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib, in lung adenocarcinoma cells harboring wild-type EGFR
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Hua Yang1,2, Rong Wang1, Shunli Peng1, Longhua Chen1, Qi Li3, Wei Wang1
1Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
2Oncology Department, Nanhai Hospital, Southern Medical University, Fuoshan, People's Republic of China
3Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
Wei Wang, e-mail: firstname.lastname@example.org
Qi Li, e-mail: email@example.com
Keywords: EGFR-TKI, drug resistance, HGF, lung cancer, wild-type EGFR
Received: September 01, 2015 Accepted: January 31, 2016 Published: February 22, 2016
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is an option for lung cancers harboring wild-type EGFR when chemotherapeutic reagents have failed. In this study, we found that the EGFR-TKI, gefitinib, modestly suppressed proliferation of the lung cancer cell lines, A549 and H358, which both harbor wild-type EGFR. Treatment with hepatocyte growth factor (HGF) reduced the sensitivity to gefitinib, whereas sensitivity was restored by treatment with an HGF antibody, a MET inhibitor, or depletion of MET but not ErbB3 gene. Moreover, both PI3K/mTOR inhibitors and MEK inhibitors suppressed proliferation of A549 cells, whereas only PI3K/mTOR inhibitors effectively suppressed cell viability of EGFR mutant PC-9 cells. Our findings suggest that HGF reduced the gefitinib sensitivity through MET and downstream PI3K and MAPK pathways. Combined use of EGFR-TKI and MET inhibitors or inhibition of downstream signaling molecules might be a better second or third line choice for a group of patients with advanced lung cancer harboring wild-type EGFR.
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