DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer
Abstract Introduction A 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 link...
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BMC
2025-03-01
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| Series: | Molecular Cancer |
| Online Access: | https://doi.org/10.1186/s12943-025-02291-0 |
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| author | Benjamin B. Morris Simon Heeke Yuanxin Xi Lixia Diao Qi Wang Pedro Rocha Edurne Arriola Myung Chang Lee Darren R. Tyson Kyle Concannon Kavya Ramkumar C. Allison Stewart Robert J. Cardnell Runsheng Wang Vito Quaranta Jing Wang John V. Heymach Barzin Y. Nabet David S. Shames Carl M. Gay Lauren A. Byers |
| author_facet | Benjamin B. Morris Simon Heeke Yuanxin Xi Lixia Diao Qi Wang Pedro Rocha Edurne Arriola Myung Chang Lee Darren R. Tyson Kyle Concannon Kavya Ramkumar C. Allison Stewart Robert J. Cardnell Runsheng Wang Vito Quaranta Jing Wang John V. Heymach Barzin Y. Nabet David S. Shames Carl M. Gay Lauren A. Byers |
| author_sort | Benjamin B. Morris |
| collection | DOAJ |
| description | Abstract Introduction A 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. Methods To 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. Results Using 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. Conclusions We 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. |
| format | Article |
| id | doaj-art-40cbbde56bd748bbaf0c60f5ee08af9f |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-40cbbde56bd748bbaf0c60f5ee08af9f2025-08-20T03:41:39ZengBMCMolecular Cancer1476-45982025-03-0124111910.1186/s12943-025-02291-0DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancerBenjamin B. Morris0Simon Heeke1Yuanxin Xi2Lixia Diao3Qi Wang4Pedro Rocha5Edurne Arriola6Myung Chang Lee7Darren R. Tyson8Kyle Concannon9Kavya Ramkumar10C. Allison Stewart11Robert J. Cardnell12Runsheng Wang13Vito Quaranta14Jing Wang15John V. Heymach16Barzin Y. Nabet17David S. Shames18Carl M. Gay19Lauren A. Byers20Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterMedical Oncology Department, Vall d’Hebron University HospitalMedical Oncology Department, Hospital del MarDepartment of Oncology Biomarker Development, Genentech IncDepartment of Pharmacology, Vanderbilt University School of MedicineDepartment of Hematology/Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Pharmacology, Vanderbilt University School of MedicineDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Oncology Biomarker Development, Genentech IncDepartment of Oncology Biomarker Development, Genentech IncDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer CenterAbstract Introduction A 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. Methods To 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. Results Using 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. Conclusions We 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.https://doi.org/10.1186/s12943-025-02291-0 |
| spellingShingle | Benjamin B. Morris Simon Heeke Yuanxin Xi Lixia Diao Qi Wang Pedro Rocha Edurne Arriola Myung Chang Lee Darren R. Tyson Kyle Concannon Kavya Ramkumar C. Allison Stewart Robert J. Cardnell Runsheng Wang Vito Quaranta Jing Wang John V. Heymach Barzin Y. Nabet David S. Shames Carl M. Gay Lauren A. Byers DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer Molecular Cancer |
| title | DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer |
| title_full | DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer |
| title_fullStr | DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer |
| title_full_unstemmed | DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer |
| title_short | DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer |
| title_sort | dna damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer |
| url | https://doi.org/10.1186/s12943-025-02291-0 |
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