Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities.

Abstract

Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in <i>EGFR</i>-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in <i>EGFR</i> ^T790M-negative resistance. We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic <i>EGFR</i>-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M⁺) and -negative (T790M^-) disease. Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M^- tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as <i>TP53</i> alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M^- tumors. Almost half of resistant tumors were further classified as immune^hot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M^- and T790M⁺ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in <i>EGFR</i>-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.