Cataloging genomic and transcriptomic features of relapsed SCLC.

8107 Background: Relapsed small cell lung cancer (R-SCLC) is characterized by poor outcomes and treatment resistance. The mechanisms driving treatment resistance in R-SCLC remain poorly understood. We comprehensively profiled R-SCLC samples along with patient-matched treatment-naive samples (TN-SCLC) using whole-exome (WES), whole-genome (WGS), and RNA-sequencing (RNA-seq) to catalog mechanisms of treatment resistance and identify actionable alterations. Methods: We analyzed 54 R-SCLC and 27 TN-SCLC samples (with 26 patient-matched TN-R pairs) using WES. At presentation, 31 patients were diagnosed with extensive and 23 with limited stage SCLC. R-SCLC samples were also analyzed by WGS (n = 28, including 18 TN-R pairs) and RNA-seq (n = 31, including 12 TN-R pairs). Differences in mutational signatures, structural variations, gene expression, alternative splicing, and neoantigen profiles were investigated between TN and R-SCLC samples. Results: R-SCLC samples contained mutation signatures characteristic of platinum exposure and APOBEC mutagenesis, which were absent in TN-SCLC. MYC family genes (MYC, MYCL, MYCN) were frequently amplified at relapse. Transcriptomic analyses revealed dysregulation of WNT signaling and IDO1. Extensive differences in alternative splicing, especially intron retention (IR), were observed (96% of all IR events were in TN-SCLC). IR in TN-SCLC affected genes involved in DNA repair, RNA metabolism, WNT and MYC pathways. TN-SCLC showed a median of 86 neoantigens, and R-SCLC 90 neoantigens per sample. TP53 was the most frequently altered gene to result in a neo-antigen (48% of analyzed samples). Immune evasion mechanisms, including upregulation of CD24 and downregulation of MHC-I, were observed in R-SCLC samples. Conclusions: This study highlights the heterogeneity of treatment resistance in SCLC, driven by genomic instability, WNT and MYC dysregulation, and splicing aberrations. Potential therapeutic strategies for R-SCLC include targeting splicing machinery, WNT signaling, and immune evasion pathways. These findings advance our understanding of SCLC biology and provide a foundation for biomarker-driven drug development.