Abstract
Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naïve (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2 -FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2 -FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide
Establishment of gefitinib-resistant cell lines To explore the novel mechanism of acquired resistance to EGF receptor (EGFR)-tyrosine kinase inhibitors (TKI), PC9 and HCC827 cells were cultured in gefitinib-containing medium
We have shown that the FGF2–FGFR1 autocrine loop is an alternative bypass track for acquired resistance to gefitinib in this study (Fig. 7)
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide. Non–small cell lung carcinoma (NSCLC) accounts for about 85% of lung cancers [1]. The median survival time of patients with advanced NSCLC is less than 1 year [2]. Owing to the recent advances in molecular-targeted therapy, the number of patients eligible for treatment with molecular-targeted drugs is increasing. EGF receptor (EGFR)-targeted therapy using EGFR-tyrosine kinase inhibitors (EGFR-TKI) for patients harboring EGFR mutations is one of the most accepted and well-studied therapies to date. EGFR mutations, such as exon 19 deletions or the L858R point mutation in exon 21, comprise the majority of mutations and are associated with sensitivity to EGFR-TKIs in NSCLC [3, 4]. 80% of the patients harboring these mutations respond well to EGFR-TKIs. almost all patients with NSCLC who initially respond well to EGFR-TKI eventually develop acquired
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