ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer
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.
Authors
- Alexandra Sexton‐Oates (ORCID: https://orcid.org/0000-0002-3841-8758)
- Irene Zamora (ORCID: https://orcid.org/0009-0004-4723-9403)
- Lynnette Fernandez‐Cuesta (ORCID: https://orcid.org/0000-0002-0724-6703)
- Alfonso Calvo (ORCID: https://orcid.org/0000-0003-4074-4242)
- María J. Pajares (ORCID: https://orcid.org/0000-0003-3149-8959)
- Miguel Barajas (ORCID: https://orcid.org/0000-0003-4004-1432)
- Mirian Gutiérrez (ORCID: https://orcid.org/0000-0002-2733-8904)
- Sungyong You (ORCID: https://orcid.org/0000-0003-3513-1783)
- Beatrice S. Knudsen (ORCID: https://orcid.org/0000-0002-7589-7591)
- R Iriarte
- Michael R. Freeman (ORCID: https://orcid.org/0000-0001-8142-3432)
- Joaquín Fernández‐Irigoyen (ORCID: https://orcid.org/0000-0001-5072-4099)
- Ignacio Encı́o (ORCID: https://orcid.org/0000-0003-1732-1989)
- Nerea Otegui (ORCID: https://orcid.org/0009-0009-7470-0847)
- Chen Qian (ORCID: https://orcid.org/0000-0002-9803-5740)
- Qian Yang (ORCID: https://orcid.org/0000-0002-2405-2396)
- Enrique Santamaría
- Luis M. Montuenga
- Nicolas Alcala
- Mirja Rotinen
Institutions
- Cedars-Sinai Medical Center (US)
- Universidad Pública de Navarra (UPNA) (ES)
- University of Utah (US)
- Navarre Institute of Health Research (ES)
- Navarrabiomed (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Centre international de recherche sur le cancer (FR)
- Universidad de Navarra (ES)
Publication Details
- Journal
- Molecular Medicine
- Published
- 2025-06-11
- DOI
- https://doi.org/10.1186/s10020-025-01267-6
- Citations
- 1
- Primary Topic
- Lung Cancer Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- Neuroendocrine Tumor Research Foundation
- Cedars-Sinai Medical Center
- Ministerio de Ciencia, Innovación y Universidades
- Ministerio de Ciencia e Innovación
- Institut National Du Cancer
- Universidad Pública de Navarra
- Centro de Investigación Biomédica en Red de Cáncer
- Instituto de Salud Carlos III
- European Regional Development Fund
- Agencia Estatal de Investigación