Abstract 1258: Deciphering evolutionary dynamics and transcriptomic adaptions under therapy in small cell lung cancer

Abstract Introduction: Small cell lung cancer (SCLC) represents a major medical challenge due to its aggressive progression and a dismal 5-year overall survival rate of only 7%. While SCLC initially responds well to chemotherapy, the rapid relapse and emergence of therapy-resistant tumors remain critical barriers to effective treatment. We hypothesized that therapy response is associated with genome evolution, which, in turn, influences transcriptional plasticity. This study aims to decipher the clonal evolution and transcriptomic adaptations in response to chemotherapy in SCLC. Methods: We established over 100 patient-derived xenotransplant models from clinical SCLC specimens, capturing diverse genetic features and clinical characteristics. A representative subset of 33 models was selected to replicate clinical scenarios in mice, modeling the effects of platinum-based chemotherapy and evaluating tumor responses under controlled conditions. Whole-exome sequencing and single-cell transcriptome profiling were performed to investigate genomic evolutionary trajectories and transcriptional plasticity in therapy-naïve and relapsed tumors. Results: Xenotransplant models accurately reflect patient responses to chemotherapy. To our surprise, several models from relapsed patients retained sensitivity to treatment. Chemotherapy-resistant models maintain their tumor clones, whereas sensitive models show dynamic shifts from a common ancestral clone with emerging subclones shaped by mutations associated with platinum damage, APOBEC activity, and defective DNA damage repair. The genomic landscape, defined by subclonal mutations and copy number alterations, strongly impacts transcriptomic patterns. Specifically sensitive models post-chemotherapy reveal a strong shift of transcriptional programs reflecting adaptive plasticity as a consequence of genome evolution. Conclusion: Here we provide an in-depth functional in vivo characterization of clonal adaptions in SCLC under therapy. Chemotherapy drives the selection of subclones with favorable genomic features, which in turn impact the broader transcriptomic landscape. Our data provides critical insights into the molecular mechanisms of therapy resistance. Citation Format: Laura Constanze Kaiser, Marcel Schmiel, Christian Müller, Maria Cartolano, Martin Peifer, Roman K. Thomas, Julie George. Deciphering evolutionary dynamics and transcriptomic adaptions under therapy in small cell 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 1258.