Adaptive cell plasticity in autocrine TGFβ2 coordinated transcriptome-metabolome reprogramming of EGFR-mutant lung cancer in precision therapy escape.

Abstract

e19043 Background: Precision therapy for advanced NSCLC with EGFR mutations is the current standard-of-care. Emergence of acquired resistance to therapy invariably occurs despite effective initial response. Classical rebiopsy studies of EGFR-mutant pts at progression have identified diverse resistance mechanisms involving T790M-EGFR, METactivation and AXL upregulation. Our studies focus on tumor cells adaptation early during therapy to map the initial course of therapeutic resistance evolution. Methods: Drug-sensitive model studies were performed usingHCC827 and PC-9 NSCLC cells under erlotinib, and H1975 cells under CL-387,785 inhibition. Affymetrix microarray profiling was performed at 0h, 8h, 9d and 9d TKI followed by 7d drug-washout. Both in vitro and in vivo xenograft analyses were conducted. Mass-spectrometry based metabolomics profiling was also conducted. Results: We identified an early adaptive drug escape in EGFR-mutant cells that emerged as early as 9 days on therapy. The prosurvival cell state...