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

Purpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in -mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in -negative resistance.

Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic -mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M) and -negative (T790M) disease.

Results: 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 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M tumors. Almost half of resistant tumors were further classified as immune, 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.

Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in -mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.