ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer
Abstract Small cell lung cancer (SCLC) is a highly aggressive malignancy with extremely poor prognosis. SCLC cells exhibit high plasticity and can progress from neuroendocrine (NE) to non-NE phenotypes. This dynamic evolution promotes treatment resistance and relapses, representing a challenge for t...
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2025-06-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01267-6 |
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| author | Mirian Gutiérrez Irene Zamora Raquel Iriarte María José Pajares Qian Yang Chen Qian Nerea Otegui Joaquín Fernández-Irigoyen Enrique Santamaría Nicolas Alcala Alexandra Sexton-Oates Lynnette Fernández-Cuesta Miguel Barajas Alfonso Calvo Luis M. Montuenga Beatrice Knudsen Sungyong You Michael R. Freeman Ignacio Encío Mirja Rotinen |
| author_facet | Mirian Gutiérrez Irene Zamora Raquel Iriarte María José Pajares Qian Yang Chen Qian Nerea Otegui Joaquín Fernández-Irigoyen Enrique Santamaría Nicolas Alcala Alexandra Sexton-Oates Lynnette Fernández-Cuesta Miguel Barajas Alfonso Calvo Luis M. Montuenga Beatrice Knudsen Sungyong You Michael R. Freeman Ignacio Encío Mirja Rotinen |
| author_sort | Mirian Gutiérrez |
| collection | DOAJ |
| description | Abstract Small cell lung cancer (SCLC) is a highly aggressive malignancy with extremely poor prognosis. SCLC cells exhibit high plasticity and can progress from neuroendocrine (NE) to non-NE phenotypes. This dynamic evolution promotes treatment resistance and relapses, representing a challenge for targeted therapies in this elusive disease. Here we identify the transcription factor ONECUT2 (OC2) as a driver of plasticity in SCLC, leading to non-NE transcriptional states. OC2 is highly expressed in SCLC tumors compared to normal lung tissue and its expression is associated with heightened clinical stage and lymph node metastasis. We show that OC2 is a repressor of ASCL1, the NE master regulator transcription factor. In addition, OC2 upregulates non-NE programs through activation of c-MYC and Notch signaling. We also demonstrate that OC2 is required for growth and survival of SCLC cells and that it can be targeted with a small molecule inhibitor that acts synergistically with the standard combination of cisplatin and etoposide, providing a novel therapeutic strategy for OC2 active SCLC tumors. |
| format | Article |
| id | doaj-art-b34f2575512b45d0af11cae442e1c977 |
| institution | DOAJ |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-b34f2575512b45d0af11cae442e1c9772025-08-20T02:39:24ZengBMCMolecular Medicine1528-36582025-06-0131111610.1186/s10020-025-01267-6ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancerMirian Gutiérrez0Irene Zamora1Raquel Iriarte2María José Pajares3Qian Yang4Chen Qian5Nerea Otegui6Joaquín Fernández-Irigoyen7Enrique Santamaría8Nicolas Alcala9Alexandra Sexton-Oates10Lynnette Fernández-Cuesta11Miguel Barajas12Alfonso Calvo13Luis M. Montuenga14Beatrice Knudsen15Sungyong You16Michael R. Freeman17Ignacio Encío18Mirja Rotinen19Department of Health Sciences, Public University of NavarreDepartment of Health Sciences, Public University of NavarreDepartment of Health Sciences, Public University of NavarreDepartment of Health Sciences, Public University of NavarreDepartment of Urology and Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Computational Biomedicine, Cedars-Sinai Medical CenterCenter for Applied Medical Research (CIMA), University of NavarraDepartment of Health Sciences, Public University of NavarreDepartment of Health Sciences, Public University of NavarreRare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research On Cancer/World Health Organization (IARC/WHO)Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research On Cancer/World Health Organization (IARC/WHO)Rare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research On Cancer/World Health Organization (IARC/WHO)Department of Health Sciences, Public University of NavarreCenter for Applied Medical Research (CIMA), University of NavarraCenter for Applied Medical Research (CIMA), University of NavarraDepartment of Pathology, University of UtahDepartment of Urology and Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Urology and Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Health Sciences, Public University of NavarreDepartment of Health Sciences, Public University of NavarreAbstract Small cell lung cancer (SCLC) is a highly aggressive malignancy with extremely poor prognosis. SCLC cells exhibit high plasticity and can progress from neuroendocrine (NE) to non-NE phenotypes. This dynamic evolution promotes treatment resistance and relapses, representing a challenge for targeted therapies in this elusive disease. Here we identify the transcription factor ONECUT2 (OC2) as a driver of plasticity in SCLC, leading to non-NE transcriptional states. OC2 is highly expressed in SCLC tumors compared to normal lung tissue and its expression is associated with heightened clinical stage and lymph node metastasis. We show that OC2 is a repressor of ASCL1, the NE master regulator transcription factor. In addition, OC2 upregulates non-NE programs through activation of c-MYC and Notch signaling. We also demonstrate that OC2 is required for growth and survival of SCLC cells and that it can be targeted with a small molecule inhibitor that acts synergistically with the standard combination of cisplatin and etoposide, providing a novel therapeutic strategy for OC2 active SCLC tumors.https://doi.org/10.1186/s10020-025-01267-6ONECUT2SCLCTumor heterogeneityPhenotypic plasticityTherapeutic target |
| spellingShingle | Mirian Gutiérrez Irene Zamora Raquel Iriarte María José Pajares Qian Yang Chen Qian Nerea Otegui Joaquín Fernández-Irigoyen Enrique Santamaría Nicolas Alcala Alexandra Sexton-Oates Lynnette Fernández-Cuesta Miguel Barajas Alfonso Calvo Luis M. Montuenga Beatrice Knudsen Sungyong You Michael R. Freeman Ignacio Encío Mirja Rotinen ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer Molecular Medicine ONECUT2 SCLC Tumor heterogeneity Phenotypic plasticity Therapeutic target |
| title | ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer |
| title_full | ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer |
| title_fullStr | ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer |
| title_full_unstemmed | ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer |
| title_short | ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer |
| title_sort | onecut2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer |
| topic | ONECUT2 SCLC Tumor heterogeneity Phenotypic plasticity Therapeutic target |
| url | https://doi.org/10.1186/s10020-025-01267-6 |
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