The repressor Capicua is a barrier to lung tumor development driven by Kras/Trp53 mutations
KRAS mutations are responsible for a quarter of all lung adenocarcinomas. However, the molecular mechanisms linking these mutations and their frequent secondary dosage amplification to tumor formation are still not fully understood. While ample evidence supports a crucial role for the MAPK pathway in tumor development, the primary effectors targeted by this pathway remain largely unexplored. Here we identify the transcriptional repressor Capicua (CIC) as a key target inactivated by KRAS/MAPK signaling in lung adenocarcinoma. We show that genetic loss of CIC recapitulates the phenotypic consequences of amplified KRAS signaling. Genetic disruption of CIC suppressed the requirement for Kras allelic imbalances and accelerated the transformation of bronchiolar Club cells. We also demonstrate that restoring CIC repressor activity impaired proliferation of CIC-deficient tumor cells and reverted resistance to MAPK pathway inhibitors. These results highlight the key role of CIC during lung tumor formation and suggest that selective pressure for effective CIC inactivation favors secondary amplification of KRAS/MAPK signaling in tumor cells.
Authors
- Marina Salmón (ORCID: https://orcid.org/0000-0003-2459-2840)
- Eduardo J. Caleiras (ORCID: https://orcid.org/0000-0001-8768-3630)
- Oksana Brehey
- Gerardo Jiménez (ORCID: https://orcid.org/0000-0003-2765-9289)
- Antonio Cebriá (ORCID: https://orcid.org/0000-0001-8222-0848)
- Carmen Blanco‐Aparicio (ORCID: https://orcid.org/0000-0002-3249-6595)
- Carmen Guerra (ORCID: https://orcid.org/0000-0002-3891-046X)
- Tirso Pons (ORCID: https://orcid.org/0000-0002-7616-7750)
- Matthias Drosten (ORCID: https://orcid.org/0000-0002-3205-456X)
- Lucía Simón-Carrasco (ORCID: https://orcid.org/0000-0002-3281-8144)
- Raúl Torres (ORCID: https://orcid.org/0000-0001-9606-0398)
- Mariano Barbacid (ORCID: https://orcid.org/0000-0002-1480-2624)
- Morena Scotece (ORCID: https://orcid.org/0000-0002-1150-2933)
- Sandra Rodríguez (ORCID: https://orcid.org/0000-0001-7221-3636)
- Carmen G. Lechuga
- Mónica Musteanu (ORCID: https://orcid.org/0000-0002-1753-3765)
- Alejandra A. Flores-Gómez
- Irene Ferrer (ORCID: https://orcid.org/0000-0001-8365-762X)
- Orlando Domı́nguez (ORCID: https://orcid.org/0000-0002-7016-6490)
- Luis Paz‐Ares
- Ivan Hernández-Navas
- Ricardo Velasco-Vicente
- Irene Ballesteros-González
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universidad Complutense de Madrid (ES)
- Research Institute Hospital 12 de Octubre (ES)
- Spanish National Cancer Research Centre (ES)
- Hospital Universitario 12 De Octubre (ES)
- Centro Nacional de Epidemiología (ES)
- Centro Nacional de Biotecnología (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Centro de Investigación Biomédica en Red (ES)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Centro de Investigación del Cáncer (ES)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (ES)
- Institut de Biologia Molecular de Barcelona (ES)
- Universidad Pablo de Olavide (ES)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1038/s44321-025-00326-z
- Primary Topic
- Developmental Biology and Gene Regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00