Abstract 5013: The interplay of genomic aberrations, transcriptional states, and therapeutic responses in lung cancer

Lung cancer leads cancer-related deaths worldwide, with 2024 estimates of 234,580 new cases in the United States. This study explores the roles of tumor driver aberrations, epithelial transcriptional states, and microenvironment composition in lung cancer outcomes using proteogenomic data from 965 patients across the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and International Cancer Proteogenome Consortium (ICPC). We examined oncogenic alterations, epithelial and stromal cell type enrichment distributions, transcriptional modules activities, and drug sensitivities in lung adenocarcinoma (LUAD), squamous carcinoma (LUSC) and adenocarcinoma with no conventional drivers (NCD-LUAD).LUAD tumors displayed mutual exclusivity in RAS/Receptor Tyrosine Kinase (RTK) pathway aberrations, complemented by significant patterns of co-occurrence and exclusivity in tumor suppressor genes like TP53, STK11, RBM10, and CDKN2A. Our integrative analysis used gene expression from single-cell RNA-seq (scRNA) derived cell types reference and CPTAC bulk RNA/proteomic data for correlation-based estimation of epithelial/stromal cell type enrichment. We assembled scRNA references from 3 different studies that profiled normal tissues containing, 142 cell types from 38 tissue types, 20 stromal cell types from 11 tissues, and lastly exclusive lung cell types reference respectively. We found significant enrichment of AT2 and Club cells in LUAD tumors (p-value < 0.0001), in addition heterogeneity in epithelial cell type enrichment within each driver group. Patients enriched for AT2 and AT1 cells demonstrated better survival outcomes (p-value < 0.0001) while, secretory Goblet and Basal cells enrichment was associated with poor survival (p-value < 0.0001), underscoring the potential link between tumor transcriptional / differentiation states and prognostic implications. NCD-LUAD showed similar epithelial cell type enrichment patterns like LUADs with known drivers while LUSC tumors show predominant basal cell enrichment. Importantly we saw specific transcriptional modules (up: E2F1,MYBL2, down: NKX2-1, NFE2L2) and cell type enrichment differences in genome unstable (high copy number burden) tumors associated with poor survival. Finally, enrichment of a myofibroblast subtype associated with survival and immune infiltration status, warrants further investigation. Cell line drug sensitivity analysis showed that the RTK-altered group with poor response to targeted therapy was enriched with undetermined differentiation transcriptional status compared to more defined cell type enrichments in the good response group (p-value = 0.016). Our study underscores the importance of multi-dimensional integrative analysis approaches of molecular, cellular, and pharmacological data to understand and advance lung cancer biology, potential cell of origin, and therapeutic strategies. Citation Format: Hanbyul Cho, Noshad Hosseini, Yi Hsiao, Rahul Mannan, Chandan Kumar-Sinha, Yuping Zhang, Gabriel Cruz, Yamei Deng, Taiwan Cancer Moonshot Program and Clinical Proteomic Tumor Analysis Consortium, Natalie Clark, Shankha Satpathy, Gilbert S. Omenn, Yu-Ju Chen, Michael Gillette, Marcin Cieslik, Saravana Dhanasekaran, Alexey I. Nesvizhskii, Arul M. Chinnaiyan. The interplay of genomic aberrations, transcriptional states, and therapeutic responses in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5013.