Targeting FGFR to Overcome EMT-Related Resistance to EGFR Inhibition in EGFR-Mutated Non-Small Cell Lung Cancer

Abstract

Acquired drug resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), therapeutic failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with resistance to EGFR TKIs in select experimental models and in the clinic, but there are no current clinical strategies to target mesenchymal EGFR-mutated NSCLC cells. This thesis presents evidence that EMT is a widespread response to EGFR inhibition in multiple in vitro and in vivo models. In both an shRNA synthetic lethality experiment and long-term drug screens interrogating EMT transcription factors, epigenetic modifiers, and receptor tyrosine kinases, I identified FGFR3 as a critical gene for the survival of EGFR mutant NSCLC cells during EGFR inhibitor therapy. Similarly, our collaborators found that knockout of FGFR1 is the top genomic target for resensitizing mesenchymal, patient derived cell lines resistant to 3rd-generation EGFR TKIs. Combining FGFR + EGFR inhibitors suppressed the emergence of drug tolerant clones with mesenchymal features prior to development of drug resistance and resensitized mesenchymal, resistant cell lines to EGFR inhibition. Finally, dual EGFR + FGFR inhibition suppressed the development of resistance in EGFR mutant NSCLC xenograft models in long term studies.