MA04.03 Osimertinib-induced Epigenetic and Transcriptional Reprogramming Drives a BRD4-POUF-PDGFRB-YAP-EMT Axis of Resistance in NSCLC

Acquired resistance to Osimertinib poses a major limitation to achieving durable therapeutic responses in NSCLCs. While multiple actionable genetic mutations have been identified, a genomic mechanism cannot be identified in >50% of resistant tumors and thus an effective second-line targeted option does not exist for these patients. Previously, we identified YAP/TEAD and ERK1/2 reactivation as two major non-mutational counter-regulatory pathways that attenuate EGFR inhibitor mediated apoptosis, promoting establishment of the drug tolerant persister (DTP) and resistant states.