Abstract A006: Differential therapeutic vulnerabilities and opportunities for smokers and never-smokers based on physiological and adaptive landscapes of lung adenocarcinoma

Abstract Tobacco smoke both has a somatic mutagenic effect and also alters the physiology and microenvironment within the lung. Physiological effects likely influence the extent to which mutations confer proliferative or survival advantages underlying oncogenesis. However, the contributions of these mutagenic and physiological effects to oncogenesis have not previously been quantified. Because the efficacy of such therapies is dependent on the adaptive benefit conferred by the targeted mutations, this quantification is crucial for the development, testing, and application of targeted therapeutics. We therefore quantified these effects in lung adenocarcinoma (LUAD) by deconvolving the prevalence of mutations in ever-smoker (ES) LUAD samples and never-smoker (NS) LUAD samples into distinct components of mutation, selection, and selective epistasis on a gene-by-gene level. Accounting for a broadly elevated mutation rate across genes in ES-LUAD, we find that several mutations—including those in KRAS, KEAP1, and STK11—contribute stronger adaptive benefits in ES-LUAD, while several others—including those in EGFR, PIK3CA, and MET—contribute stronger adaptive benefits in NS-LUAD. Examining the strength of pairwise selective epistasis, we find that tobacco smoke alters epistatic relationships within LUAD: ES-LUAD exhibits more frequent synergy of adaptive effects, and markedly less frequent antagonism. We also find an underappreciated role for higher-order epistasis in guiding the evolution of cancer, including frequent sub-additive higher-order epistasis, and instances of emergent synergistic interactions between multiple mutations. We provide even greater nuance to the effect of tobacco smoke on the adaptive benefit of mutations by quantifying the adaptive effects of somatic mutations across a continuous spectrum of tobacco smoke burden. We then identify the molecular pathways implicated in the altered adaptive landscape of ES-LUAD. Finally, we quantify the power of measures of adaptive effects in the contexts of smoking history and epistasis to predict differential patient response to targeted therapeutics and response of experimental models to gene inhibition. Our inference that mutations of EGFR contribute a multi-fold greater adaptive benefit in NS-LUAD than in ES-LUAD predicts a stronger response to EGFR inhibitors among never-smokers than ever-smokers, a result validated by numerous clinical studies. This analysis demonstrates that tobacco smoke alters the adaptive landscape of LUAD. It also provides quantitative measures of the adaptive benefit conferred by mutations to oncogenesis across somatic genetic backgrounds and burdens of tobacco smoke. These measures facilitate precision medicine both by informing the development and testing of targeted therapeutics—for example by identifying high effect mutations or biomarkers of response to new targeted therapeutics—as well as by providing predictions of genetic vulnerabilities that can be further explored through functional genetic approaches in experimental models. Citation Format: Krishna Dasari, Jorge A Alfaro-Murillo, Jeffrey P Townsend. Differential therapeutic vulnerabilities and opportunities for smokers and never-smokers based on physiological and adaptive landscapes of lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A006.