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Peer-reviewedCC BY 4.0Cell Reports Medicine

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

  • Rajesh Kumar1
  • Parth Desai1,2
  • Rajaa El Meskini3
  • Chirayu Mohindroo1,4
  • Alexandra Ágnes Benő5
  • Devon Atkinson3
  • Michael Nirula1
  • Laura Bassel3
  • Nobuyuki Takahashi1,6
  • Kelly L. Sovacool7,8
  • Anna Meinhardt1
  • Mohit Arora1
18 more authors
  • Kanak Parmar1
  • Darryl Nausome7
  • Samantha Nichols1
  • Linda Sciuto1
  • Shannon Swift9
  • Kolos Nemes5
  • Ajit Kumar Sharma1
  • Nathan Pate3
  • Arun Rajan9
  • Elliot Levy10
  • Michael Kassin10
  • Christopher Febres Aldana11
  • Vishal Koparde7,8
  • Melissa Galloux12
  • Roshan Shreshta1
  • Zoe Weaver Ohler3
  • Lorinc Pongor5
  • Anish Thomas1,13
13 affiliations
  1. 1Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  2. 2Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
  3. 3Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
  4. 4Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
  5. 5Cancer Genomics and Epigenetics Core Group, Hungarian Centre of Excellence for Molecular Medicine, Szeged, Hungary
  6. 6Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
  7. 7Collaborative Bioinformatics Resource, Center for Cancer Research, National Cancer Institute/National Institutes of Health, Bethesda, MD, USA
  8. 8Advanced Biomedical Computational Science, Frederick National Laboratory Research, Frederick, MD, USA
  9. 9Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
  10. 10Interventional Radiology, National Institutes of Health Clinical Center, Bethesda, MD, USA
  11. 11Laboratory of Pathology, National Institutes of Health Clinical Center, Bethesda, MD, USA
  12. 12Independent Bioinformatician, Marseille, France
  13. 13Robert H. Lurie Comprehensive Cancer Center and Division of Hematology and Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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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.

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Cite

BibTeXRIS
BibTeX
@article{kumar2026stemlike,
  title = {{A stem-like chromatin program in small-cell lung cancer is associated with poor outcomes after chemoimmunotherapy}},
  author = {Rajesh Kumar and Parth Desai and Rajaa El Meskini and Chirayu Mohindroo and Alexandra Ágnes Benő and Devon Atkinson and Michael Nirula and Laura Bassel and Nobuyuki Takahashi and Kelly L. Sovacool and Anna Meinhardt and Mohit Arora and Kanak Parmar and Darryl Nausome and Samantha Nichols and Linda Sciuto and Shannon Swift and Kolos Nemes and Ajit Kumar Sharma and Nathan Pate and Arun Rajan and Elliot Levy and Michael Kassin and Christopher Febres Aldana and Vishal Koparde and Melissa Galloux and Roshan Shreshta and Zoe Weaver Ohler and Lorinc Pongor and Anish Thomas},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = sep,
  doi = {10.1016/j.xcrm.2026.103027},
  url = {https://doi.org/10.1016/j.xcrm.2026.103027},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A stem-like chromatin program in small-cell lung cancer is associated with poor outcomes after chemoimmunotherapy
AU  - Rajesh Kumar
AU  - Parth Desai
AU  - Rajaa El Meskini
AU  - Chirayu Mohindroo
AU  - Alexandra Ágnes Benő
AU  - Devon Atkinson
AU  - Michael Nirula
AU  - Laura Bassel
AU  - Nobuyuki Takahashi
AU  - Kelly L. Sovacool
AU  - Anna Meinhardt
AU  - Mohit Arora
AU  - Kanak Parmar
AU  - Darryl Nausome
AU  - Samantha Nichols
AU  - Linda Sciuto
AU  - Shannon Swift
AU  - Kolos Nemes
AU  - Ajit Kumar Sharma
AU  - Nathan Pate
AU  - Arun Rajan
AU  - Elliot Levy
AU  - Michael Kassin
AU  - Christopher Febres Aldana
AU  - Vishal Koparde
AU  - Melissa Galloux
AU  - Roshan Shreshta
AU  - Zoe Weaver Ohler
AU  - Lorinc Pongor
AU  - Anish Thomas
PY  - 2026
DA  - 2026/09/10
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103027
UR  - https://doi.org/10.1016/j.xcrm.2026.103027
AB  - 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.
SN  - 2666-3791
ER  -