2. Academic Validation
  3. The repressor Capicua is a barrier to lung tumor development driven by Kras/Trp53 mutations

The repressor Capicua is a barrier to lung tumor development driven by Kras/Trp53 mutations

  • EMBO Mol Med. 2025 Dec;17(12):3377-3406. doi: 10.1038/s44321-025-00326-z.
Irene Ballesteros-González 1 2,  Iván Hernández-Navas 3 4 5,  Oksana Brehey 6,  Carmen G Lechuga 6,  Marina Salmón 6,  Morena Scotece 1 2,  Ricardo Velasco-Vicente 1 2,  Alejandra A Flores-Gómez 1 2,  Antonio Cebriá 7,  Lucía Simón-Carrasco 6 8 9,  Gerardo Jiménez 10 11,  Monica Musteanu 5 12,  Carmen Guerra 5 6,  Orlando Domínguez 13,  Eduardo Caleiras 14,  Carmen Blanco-Aparicio 7,  Tirso Pons 15,  Irene Ferrer 3 4 5,  Luis Paz-Ares 5 16 17,  Raul Torres-Ruiz 18 19 20 21,  Sandra Rodríguez-Perales 18,  Mariano Barbacid 5 6,  Matthias Drosten 22 23 24
Affiliations

Affiliations

  • 1 Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), 37007, Salamanca, Spain.
  • 2 Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-USAL, 37007, Salamanca, Spain.
  • 3 Grupo de Terapias Dirigidas para la Oncología de Precisión & Unidad de Investigación Clínica de Cáncer de Pulmón, Instituto de Investigación Hospital 12 de Octubre, 28041, Madrid, Spain.
  • 4 Clinical Research Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain.
  • 5 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain.
  • 6 Tumor Biology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain.
  • 7 Experimental Therapeutics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain.
  • 8 Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Sevilla, 41092, Sevilla, Spain.
  • 9 Universidad Pablo de Olavide, 41013, Sevilla, Spain.
  • 10 Instituto de Biología Molecular de Barcelona (IBMB), CSIC, 08028, Barcelona, Spain.
  • 11 Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain.
  • 12 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, 28040, Madrid, Spain.
  • 13 Genomics Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain.
  • 14 Histopathology Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain.
  • 15 Department of Immunology and Oncology, National Center for Biotechnology (CNB-CSIC), Spanish National Research Council, 28049, Madrid, Spain.
  • 16 Unidad de Investigación Clínica de Cáncer de Pulmón, Instituto de Investigación Hospital 12 de Octubre, 28041, Madrid, Spain.
  • 17 Complutense University of Madrid, 28040, Madrid, Spain.
  • 18 Molecular Cytogenetics and Genome Editing Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029, Madrid, Spain.
  • 19 Division of Hematopoietic Innovative Therapies, Biomedical Innovation Unit, Centro de Investigaciones Energéticas, Medioambientales, y Tecnológicas (CIEMAT), 28040, Madrid, Spain.
  • 20 Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28003, Madrid, Spain.
  • 21 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029, Madrid, Spain.
  • 22 Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), 37007, Salamanca, Spain. [email protected].
  • 23 Instituto de Biología Molecular y Celular del Cáncer (IBMCC), CSIC-USAL, 37007, Salamanca, Spain. [email protected].
  • 24 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain. [email protected].
PMID: 41219537 DOI: 10.1038/s44321-025-00326-z
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.

Keywords

Allelic Imbalance; Drug Resistance; KRAS; Lung Cancer; Repression.

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