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

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 Vidal, Juan Sendón-Lago, Marina Rodriguez-Candela Mateos, José R. Caeiro, Victoria Sanz-Moreno, Trond Aasen, Miguel G. Blanco, Guadalupe Sabio, María Quindós, Carmen Rivas, David Santamaría, Carlos Fernandez-Lozano, Eduardo Fonseca, Pablo Huertas, Berta Sánchez-Laorden, Constance Alabert and María D. Mayán ()
Additional contact information
Adrián Varela-Vázquez: Universidade da Coruña (UDC), A Coruña, Spain)
Amanda Guitián-Caamaño: Universidade da Coruña (UDC), A Coruña, Spain)
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
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)
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)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60971-3

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