2013 Fiscal Year Final Research Report

Investigation of the mechanism of gefitinib resistance by comprehensive genetic analysis

Research Project

Project/Area Number	24790822
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Respiratory organ internal medicine
Research Institution	Keio University
Principal Investigator	TERAI Hideki 慶應義塾大学, 医学部, 助教 (50445293)
Project Period (FY)	2012-04-01 – 2014-03-31
Keywords	EGFR-TKI / 肺癌 / 薬剤耐性 / イレッサ / ゲフィチニブ
Research Abstract	Almost all patients with non-small cell lung cancer who harbor an epidermal growth factor receptor (EGFR) mutation initially respond well to EGFR-tyrosine kinase inhibitors (TKIs) eventually experience relapse. In this study, we have established a gefitinib-resistant cell line model by long-term exposure to gefitinib. We used originally gefitinib-sensitive lung cancer cell lines, namely PC9 and HCC827. We found that the expressions of both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells compared to those in PC9 naïve (PC9 na) cells. We found that proliferation of the PC9 GR cells was dependent on FGF2-FGFR1 pathway. Inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored the gefitinib sensitivity in PC9 GR cells. We propose FGF2-FGFR1 activation through autocrine loop is a novel mechanism of acquiring resistance to EGFR-TKIs and that this loop be targeted to overcome acquired resistance to EGFR-TKIs in a subset of NSCLC patients.