Abstract 6943: Evolutionary dynamics under chemotherapy in small cell lung cancer: Insights from patient-derived xenotransplant models

Abstract Introduction: The treatment of patients with small cell lung cancer (SCLC) represents a major medical challenge due to aggressive tumor growth and the poor 5-year overall survival rate of only 5%. SCLC tumors typically are remarkably sensitive to chemotherapy at the beginning; however, the subsequent rapid relapse of therapy-resistant tumors is a severe obstacle. We therefore aimed to decipher the molecular patterns guiding processes of evolutionary adaptation in SCLC as a consequence of therapeutic interventions. Methods: Over 100 patient-derived xenotransplant models were generated from clinical SCLC specimens capturing a wide range of genetic and molecular features as well as clinical phenotypes with regard to chemotherapy response. We recapitulated chemotherapy response in vivo for 32 models, and performed in-depth genome and single-cell transcriptome sequencing to thus dissect genomic evolutionary trajectories and transcriptional plasticity of therapy-naïve and relapsed tumors, which includes the study of multiregional and longitudinal samples. Results: The response to chemotherapy in vivo reflected the clinical response of the patients; however, several models of relapsed patients remained sensitive to treatment. Genomic studies of clonal dynamics indicated selection of subclones as a result of therapeutic pressure. In contrast, chemo-refractory tumors maintained their clonal composition after therapy. In agreement with genomic profiles, single-cell transcriptome data revealed a tremendous shift in expression profiles and composition of subpopulations. Furthermore, subclonal genomic events including copy number alterations were found to shape the transcriptional heterogeneity in tumors. Conclusion: Here, we demonstrate a comprehensive functional characterization of multi-regional tumor sites and longitudinal specimens acquired from patients with SCLC, in which we elucidate genomic and transcriptional heterogeneity as a consequence of therapy response. Overall, our data points to a complex interplay between sub-clonal genomic changes and transcriptional plasticity shaping therapy response in which pre-existing genomic alterations impact selection under therapy. Citation Format: Laura C. Kaiser, Marcel Schmiel, Agnieszka Ruminska, Nazanin Alavinejad, Christian Müller, Justinas Valiulis, Martin Peifer, Maria Cartolano, Roman K. Thomas, Julie George. Evolutionary dynamics under chemotherapy in small cell lung cancer: Insights from patient-derived xenotransplant models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6943.