Journal
MOLECULAR CANCER RESEARCH
Volume 11, Issue 7, Pages 759-767Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-12-0652
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [22590870, 24790822, 23501311]
- Grants-in-Aid for Scientific Research [22590870, 24790822, 23501311] Funding Source: KAKEN
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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 naive (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.
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