ArticleMolecular cancer2025
DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer.
Article in Molecular cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- BraMARS: An Interpretable Histopathology-Driven Deep Learning Model for Brain Metastasis Risk Stratification in Surgically Resected Limited-Stage SCLC.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- TONSL promotes hepatocellular carcinoma progression and radioresistance by orchestrating DNA damage repair and cell cycle dynamics.Discover oncology · 2026Article
- Review
- KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage.bioRxiv : the preprint server for biology · 2026Article
- Prognostic impact of baseline blood biomarkers in SCLC first-line treatment.Therapeutic advances in medical oncology · 2026Article
- DNA damage response and cell fate decisions across the lifespan: from fetal development to age-related respiratory diseases.Cell & bioscience · 2025Review
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Authors and funding
21 authors.
Funding
Abstract
introductionA hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes.
methodsTo study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is associated with SCLC biology, chemotherapy response, and tumor evolution following therapy.
resultsUsing multi-omic profiling, we demonstrate that SCLC tumors cluster into three DDR phenotypes with unique molecular features. Hallmarks of these DDR clusters include differential expression of DNA repair genes, increased replication stress, and heightened G2/M cell cycle arrest. SCLCs with elevated DDR phenotypes exhibit increased neuroendocrine features and decreased "inflamed" biomarkers, both within and across SCLC subtypes. Clinical analyses demonstrated treatment naive DDR status was associated with different responses to frontline chemotherapy. Using longitudinal liquid biopsies, we found that DDR Intermediate and High tumors exhibited subtype switching and coincident emergence of heterogenous phenotypes following frontline treatment.
conclusionsWe establish that SCLC can be classified into one of three distinct, clinically relevant DDR clusters. Our data demonstrates that DDR status plays a key role in shaping SCLC phenotypes and may be associated with different chemotherapy responses and patterns of tumor evolution. Future work targeting DDR specific phenotypes will be instrumental in improving patient outcomes.
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