Rajesh Kumar, Parth Desai, Rajaa El Meskini, Chirayu Mohindroo, Alexandra Ágnes Benő, Devon Atkinson, Michael Nirula, Laura Bassel, Nobuyuki Takahashi, Kelly L Sovacool, Anna Meinhardt, Mohit Arora, Kanak Parmar, Darryl Nausome, Samantha Nichols, Linda Sciuto, Shannon Swift, Kolos Nemes, Ajit Kumar Sharma, Nathan Pate, Arun Rajan, Elliot Levy, Michael Kassin, Christopher Febres Aldana, Vishal Koparde, Melissa Galloux, Roshan Shreshta, Zoe Weaver Ohler, Lorinc Pongor, Anish Thomas
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.