Treatment of NSCLC patients harboring activating EGFR mutations with EGFR TKIs results in anti-tumor responses to therapy, however patients ultimately progress on therapy due to the acquisition of drug resistance. Known mechanisms of resistance include secondary mutations in the EGFR gene (EGFRT790M) or MET gene amplification, however the underlying mechanism of resistance remains to be elucidated in ∼40-45% of cases. Previous studies provide evidence for an epithelial-to-mesenchymal transition (EMT) in a subset of cases that is not associated with the known mechanisms of resistance. In this study, we identify 2 models of acquired resistance to erlotinib that are associated with an EMT phenotype and a dependence on autocrine FGF-FGFR signaling for resistance. Evidence for FGFR pathway activation in the erlotinib-resistant cell population included an increase in FGF2, FGFR1 and phospho-FRS2. Inhibition of FGFR signaling using a small molecule kinase inhibitor or FGFR1-Fc neutralization of FGFR1 ligands re-sensitized resistant cells to erlotinib. Re-sensitization was accompanied by an inhibition of downstream signaling. In contrast, inhibition of AXL, a kinase that has recently been identified as an EMT-associated driver of erlotinib resistance in some pre-clinical models, failed to re-sensitize erlotinib-resistant cells. Our findings are consistent with autocrine FGFR pathway activation, as FGF ligand neutralization in the absence of an exogenous source of ligand can re-sensitize cells to erlotinib. Finally, FGFR pathway inhibition suppressed the development of resistance to erlotinib in sensitive parental cells. These data indicate that FGFR activation could potentially serve as a mechanism of acquired resistance to erlotinib in cases associated with an EMT and suggest that combined inhibition of EGFR and FGFR signaling could be beneficial in treating such cases.

Citation Format: Xiaofen Ye, Peng Yue, Rajesh Patel, Zora Modrusan, Jeff Settleman, Avi Ashkenazi, Robert L. Yauch. Activation of FGFR signaling as a mechanism of acquired resistance to erlotinib in EGFR-mutant lung cancer associated with an EMT. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4463. doi:10.1158/1538-7445.AM2013-4463