Investigation of the mechanism of gefitinib resistance by comprehensive genetic analysis

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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.