LAUSR

Epithelial-to-mesenchymal transition (EMT) has been identified as a mechanism of both adaptive and acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in in vitro models and clinical samples of EGFR-mutated non-small cell lung cancer (NSCLC). However, a therapeutic strategy for targeting this mechanism remains unknown. In the setting of adaptive resistance early in the course of EGFR treatment, we observed that FGFR3 upregulation coincided with increased expression of mesenchymal genes, and a pooled shRNA dropout screen identified FGFR3 as a top sensitizer to EGFR inhibitor treatment. Dual FGFR (BGJ398) and EGFR (gefitinib) inhibition suppressed the outgrowth of drug-tolerant persister clones compared to EGFR TKI alone in vitro. Finally, we observed that the combination of BGJ398 and gefitinib prevented the development of in vivo resistance in PC9 xenograft mouse models. These results suggest that dual FGFR-EGFR blockade may be an effective strategy for preventing resistance associated with EMT in EGFR mutant NSCLC. Citation Format: Sana Raoof, David Ruddy, Daria Timonia, Leah Damon, Jeff Engelman, Aaron Hata. Targeting FGFR to overcome EMT-related resistance in EGFR-mutated non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A142.