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A stem-like chromatin program in small-cell lung cancer is associated with poor outcomes after chemoimmunotherapy
Journal article   Open access   Peer reviewed

A stem-like chromatin program in small-cell lung cancer is associated with poor outcomes after chemoimmunotherapy

Rajesh Kumar, Parth Desai, Rajaa El Meskini, Chirayu Mohindroo, Alexandra Ágnes Benő, Devon Atkinson, Michael Nirula, Laura Bassel, Nobuyuki Takahashi, Kelly L Sovacool, …
Cell reports. Medicine, 103027
09/10/2026
DOI: 10.1016/j.xcrm.2026.103027
PMID: 42721975
url
https://doi.org/10.1016/j.xcrm.2026.103027View
Published (Version of record) Open Access

Abstract

Small-cell lung cancer (SCLC) is an aggressive malignancy with substantial tumor heterogeneity and limited clinically actionable biomarkers beyond established features such as liver metastases. We profile tumor-intrinsic chromatin accessibility in a patient-derived xenograft biobank and identify three recurrent chromatin programs: neuroendocrine, marked by ASCL1/NEUROD1 activity; immunogenic, marked by IRF-associated activity; and stem-like, marked by TEAD/OCT activity. These programs are reproduced at the cohort level across bulk and single-cell transcriptomic datasets comprising more than 800 tumors, including 300 extensive-stage samples. In patients treated with chemoimmunotherapy, the stem-like program is associated with inferior survival, including a median overall survival of 7.41 months versus 15.9 and 12.6 months for immunogenic and neuroendocrine groups, respectively. This association remains significant after adjustment for liver metastases, brain metastases, and elevated lactate dehydrogenase. These findings support a high-risk stem-like SCLC chromatin program for prospective biomarker refinement and therapeutic investigation.
 Plasticity chemoimmunotherapy small-cell lung cancer PDX chromatin accessibility regulatory programs multi-omics stem-like tumor state biomarker ATAC-seq

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