The repressor Capicua is a barrier to lung tumor development driven by Kras/Trp53 mutations
Year: 2025
Type: article
Abstract: 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.
Source: EMBO Molecular Medicine
Authors: Irene Ballesteros-González, Iván Hernández-Navas, Oksana Brehey, Carmen G Lechuga, Marina Salmón, Morena Scotece, Ricardo Velasco-Vicente, Alejandra A Flores-Gómez, Antonio Cebriá, Lucía Simón-Carrasco, Gerardo Jiménez, Monica Musteanu, Carmen Guerra, Orlando Domínguez, Eduardo Caleiras, Carmen Blanco-Aparicio, Tirso Pons, Irene Ferrer, Luis Paz-Ares, Raul Torres-Ruiz, Sandra Rodríguez-Perales, Mariano Barbacid, Matthias Drosten
Institutions: Universidad de Salamanca, Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer de Salamanca, Instituto de Salud Carlos III, Research Institute Hospital 12 de Octubre, Spanish National Cancer Research Centre, Hospital Universitario 12 De Octubre, Centro de Investigación Biomédica en Red de Cáncer, Consejo Superior de Investigaciones Científicas, Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla, Universidad Pablo de Olavide, Institució Catalana de Recerca i Estudis Avançats, Institut de Biologia Molecular de Barcelona, Universidad Complutense de Madrid, Centro Nacional de Biotecnología, Centre for Biomedical Network Research on Rare Diseases, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Instituto de Investigación Sanitaria Fundación Jiménez Díaz
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
Awards: G1395352219, G2724019760, G2728584129, G2778915863, G3604014560, Mejora del tratamiento del cáncer mediante activación in vivo de muerte celular inmunogénica usando de forma combinada LNP y CRISPR dirigidas contra amplificaciones de oncogenes, G3986678260, G4158849155, Desarrollo de aproximaciones de terapia génica lentiviral y edición génica para el tratamiento de transtornos plaquetarios congenitos, G6223164701, G6240272025, G694919430, G8163712750, G8349547568
OpenAlex ID: W4416109254