Clinicogenomic analysis of EGFR -mutant lung tumors identifies Rb pathway inactivation as a hallmark of squamous transformation

作者：Alexandria Dymun, Mark Jeng, Arielle Elkrief, Harshita Mehrotra, Soo-Ryum Yang, Christina E. Wilson, Natasha Rekhtman, Irina Linkov, Amanda Pupo, Christina J. Falcon, Clare Wilhelm, Parvathy Manoj, 钟竑, Harsha Sridhar, Mark G. Kris, Nicholas D. Socci, Juan Qiu, Elisa de Stanchina, Allison L. Richards, Mark T.A. Donoghue, Charles M. Rudin, Helena A. Yu, Àlvaro Quintanal-Villalonga · 发表于：Science Translational Medicine · 年份：2026 · DOI：10.1126/scitranslmed.aea4881 · 被引用次数：1 · 研究领域：Lung Cancer Treatments and Mutations、Cancer-related Molecular Pathways、Lung Cancer Research Studies

Histologic transformation to lung squamous cell carcinoma (LUSC) is an underrecognized mechanism of resistance in epidermal growth factor receptor ( EGFR )–mutant lung adenocarcinoma (LUAD). Although AKT and MYC activation have been linked to LUSC features, the clinicogenomic determinants of this transformation remain undefined. In this study, we performed comprehensive clinical and multiomic profiling—including genomic, transcriptomic, methylation, and proteomic analyses—of EGFR -mutant tumors that were transforming, adenosquamous (LUAS), or de novo LUSC. Patients with EGFR -mutant LUSC or LUAS had shorter overall survival on first-line osimertinib compared with those with EGFR -mutant LUAD. Transforming tumors were enriched for alterations in the retinoblastoma (Rb) and AKT pathways, particularly cyclin-dependent kinase inhibitor 2A/B ( CDKN2A/B ) deletions. These alterations were also frequent in EGFR –wild-type LUSC and associated with shorter time-to-osimertinib discontinuation. In genetically engineered human in vivo models, Rb inactivation, in combination with AKT and MYC activation, enhanced the acquisition of LUSC features. Single-cell RNA profiling of such models recapitulated the molecular changes observed in the transforming clinical specimens and identified MET pathway up-regulation during transformation. Combined EGFR and MET inhibition suppressed tumor growth in patient-derived xenograft models of LUSC transformation. Together, these findings highlight Rb pathw...