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OA01.01: Tumor-Intrinsic Epigenetic States Uncover a Stem-Like SCLC Predictive of Chemoimmunotherapy Failure
Abstract   Peer reviewed

OA01.01: Tumor-Intrinsic Epigenetic States Uncover a Stem-Like SCLC Predictive of Chemoimmunotherapy Failure

Rajesh Kumar, Parth Desai, Rajaa El Meskini, Chirayu Mohindroo, Alexandra Ágnes Benő, Devon Atkinson, Micheal Nirula, Nobuyuki Takahashi, Kelly L. Sovacool, Anna Meinhardt, …
Journal of thoracic oncology, Vol.21(7 Suppl. 1), 103996
07/2026
DOI: 10.1016/j.jtho.2026.103996

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Abstract

Background Small-cell lung cancer (SCLC) remains a highly lethal malignancy with substantial intertumoral heterogeneity and no validated biomarkers capable of guiding treatment selection. Transcriptome-based classifications have been limited by stromal contamination and inconsistent predictive value, particularly in the era of first-line chemo-immunotherapy (chemo-IO). We sought to define tumor-intrinsic subtypes of SCLC through chromatin accessibility profiling and evaluate their clinical relevance across disease stages and therapeutic contexts. Methods We performed ATAC-seq on 39 patient-derived xenografts (PDXs) with matched RNA-seq to identify chromatin-informed molecular programs. We derived subtype-specific gene signatures linked to highly variable ATAC peaks and validated these signatures across >800 tumors, including early- and extensive-stage SCLC, newly profiled relapsed tumors, and single-cell RNA-seq from 19 human tumors. Subtype associations with survival were assessed in treatment-naïve extensive-stage SCLC from the IMpower133 trial. Results ATAC-seq profiling of 39 SCLC patient-derived xenografts revealed three reproducible tumor-intrinsic subtypes: neuroendocrine (SCLC-NE), immunogenic (SCLC-IM), and a previously unrecognized stem-like, immune-excluded subtype (SCLC-SL). SCLC-NE showed ASCL1/NEUROD1-driven chromatin accessibility, SCLC-IM exhibited IRF-associated immune activation, and SCLC-SL was defined by TEAD/POU-driven regulatory programs with enrichment of MYC targets, mTORC1 signaling, glycolysis, and hypoxia (Figure A, B). Matched RNA-seq confirmed that chromatin accessibility translated into distinct transcriptional programs. These subtypes were validated across >800 tumors—including early-stage, extensive-stage, and >300 newly profiled relapsed samples—and were preserved at single-cell resolution, with SCLC-SL demonstrating the least differentiated state by CytoTRACE. Application to IMpower133 showed that SCLC-SL had significantly inferior survival following chemo-immunotherapy (median OS 7.4 vs. 15.9 [IM] and 12.6 months [NE]; P<0.001) (Figure C) and remained an independent predictor after adjustment for liver/brain metastases and LDH. Prior transcriptomic classifications did not predict outcome, whereas the chromatin-based classifier uniquely identified SCLC-SL as a high-risk group that expands well beyond POU2F3-enriched tumors (Figure D). Analysis of paired pre- and post-treatment samples showed enrichment of SCLC-SL after therapy, suggesting treatment-associated selection of stem-like states.

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