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Cx43 enhances response to BRAF/MEK inhibitors by reducing DNA repair capacity

Author

Listed:
  • Adrián Varela-Vázquez

    (Universidade da Coruña (UDC), A Coruña, Spain)
    The Institute of Cancer Research)

  • Amanda Guitián-Caamaño

    (Universidade da Coruña (UDC), A Coruña, Spain)
    University College Dublin)

  • Paula Carpintero-Fernández

    (Universidade da Coruña (UDC), A Coruña, Spain))

  • Alexander Carneiro-Figueira

    (Universidade da Coruña (UDC), A Coruña, Spain))

  • Vanesa Álvarez

    (University of Dundee)

  • Marta Varela-Eirín

    (Universidade da Coruña (UDC), A Coruña, Spain))

  • Teresa Calleja-Chuclá

    (Universidade da Coruña (UDC))

  • Susana B. Bravo-López

    (Universidade de Santiago de Compostela (USC))

  • Anxo Vidal

    (Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS))

  • Juan Sendón-Lago

    (Universidade de Santiago de Compostela)

  • Marina Rodriguez-Candela Mateos

    (Universidade da Coruña (UDC))

  • José R. Caeiro

    (Universidade de Santiago de Compostela (USC))

  • Victoria Sanz-Moreno

    (The Institute of Cancer Research)

  • Trond Aasen

    (Autonomous University of Barcelona, CIBERONC)

  • Miguel G. Blanco

    (Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS))

  • Guadalupe Sabio

    (Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS))

  • María Quindós

    (Universidade da Coruña (UDC))

  • Carmen Rivas

    (Universidade de Santiago de Compostela
    Consejo Superior de Investigaciones Científicas (CSIC))

  • David Santamaría

    (Centro de Investigación del Cáncer, CSIC. University of Salamanca)

  • Carlos Fernandez-Lozano

    (Universidade da Coruna)

  • Eduardo Fonseca

    (Universidade da Coruña (UDC), A Coruña, Spain)
    Universidade da Coruña (UDC))

  • Pablo Huertas

    (Universidad de Sevilla-Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide)

  • Berta Sánchez-Laorden

    (Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández)

  • Constance Alabert

    (University of Dundee)

  • María D. Mayán

    (Universidade da Coruña (UDC), A Coruña, Spain))

Abstract

BRAF and MEK inhibitors (BRAF/MEKi) have radically changed the treatment landscape of advanced BRAF mutation-positive tumours. However, limited efficacy and emergence of drug resistance are major barriers for successful treatments. Here, by using relevant preclinical models, we find that Connexin43 (Cx43), a protein that plays a role in cell-to-cell communication, enhances the effectiveness of BRAF/MEKi by recruiting DNA repair complexes to lamin-associated domains and promoting persistent DNA damage and cellular senescence. The nuclear compartmentalization promoted by Cx43 contributes to genome instability and synthetic lethality caused by excessive DNA damage, which could provide a therapeutic approach for these tumours to overcome drug resistance. Based on these findings, we designed a drug combination using small extracellular vesicles (sEVs) to deliver the full-Cx43 in combination with the BRAF/MEKi. This study reveals Cx43 as a regulator of DNA repair and BRAF/MEKi response, highlighting the therapeutic potential that this approach could eventually have in the clinic to overcome the limitations of current therapies and improve treatment outcomes for patients with advanced BRAF mutant tumours.

Suggested Citation

  • Adrián Varela-Vázquez & Amanda Guitián-Caamaño & Paula Carpintero-Fernández & Alexander Carneiro-Figueira & Vanesa Álvarez & Marta Varela-Eirín & Teresa Calleja-Chuclá & Susana B. Bravo-López & Anxo V, 2025. "Cx43 enhances response to BRAF/MEK inhibitors by reducing DNA repair capacity," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60971-3
    DOI: 10.1038/s41467-025-60971-3
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