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Updated: Jan 11, 2026

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

Irene Ballesteros-González1,2, Iván Hernández-Navas3,4,5, Oksana Brehey6

  • 1Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), 37007, Salamanca, Spain.

EMBO Molecular Medicine
|November 11, 2025
PubMed

Insights

KRAS mutations drive lung cancer by inactivating the Capicua (CIC) protein. Restoring CIC function halts tumor growth and overcomes resistance to MAPK inhibitors, revealing CIC as a key player in lung adenocarcinoma development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS mutations are common in lung adenocarcinoma, but downstream mechanisms are unclear.
  • The MAPK pathway is implicated, yet primary effectors remain unidentified.
  • Understanding these pathways is crucial for targeted lung cancer therapies.

Purpose of the Study:

  • To identify key effectors of KRAS/MAPK signaling in lung adenocarcinoma.
  • To investigate the role of the transcriptional repressor Capicua (CIC) in tumor formation.
  • To explore CIC as a potential therapeutic target in lung cancer.

Main Methods:

  • Genetic analysis of CIC and KRAS in lung adenocarcinoma models.
  • Cellular assays to assess proliferation and drug resistance.
  • In vivo studies using mouse models of lung cancer.

Main Results:

  • Loss of CIC function mimics KRAS amplification effects in lung adenocarcinoma.
  • CIC inactivation accelerates tumor formation and bypasses the need for Kras amplification.
  • Restoring CIC activity inhibits proliferation and drug resistance in CIC-deficient tumors.

Conclusions:

  • CIC is a critical target inactivated by KRAS/MAPK signaling in lung adenocarcinoma.
  • CIC inactivation is a key driver of lung tumor development.
  • Targeting CIC may offer a novel therapeutic strategy for lung cancer, particularly in overcoming resistance to MAPK inhibitors.
Keywords:
Allelic ImbalanceDrug ResistanceKRASLung CancerRepression

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