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; María D. Mayán

doi:10.1038/s41467-025-60971-3

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-LozanoEduardo Fonseca, Pablo Huertas, Berta Sánchez-Laorden, Constance Alabert, María D. Mayán (Lead / Corresponding author)

Molecular Cell and Developmental Biology

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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.

Original language	English
Article number	6168
Number of pages	20
Journal	Nature Communications
Volume	16
Early online date	4 Jul 2025
DOIs	https://doi.org/10.1038/s41467-025-60971-3
Publication status	E-pub ahead of print - 4 Jul 2025

Keywords

Connexin 43/metabolism
DNA Repair/drug effects
Proto-Oncogene Proteins B-raf/antagonists & inhibitors
Humans
Cell Line, Tumor
Protein Kinase Inhibitors/pharmacology
Animals
DNA Damage/drug effects
Mice
Drug Resistance, Neoplasm/drug effects
Extracellular Vesicles/metabolism
Mutation
Cellular Senescence/drug effects

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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Varela-Vázquez, A., Guitián-Caamaño, A., Carpintero-Fernández, P., Carneiro-Figueira, A., Álvarez, V., Varela-Eirín, M., Calleja-Chuclá, T., Bravo-López, S. B., Vidal, A., Sendón-Lago, J., Mateos, M. R.-C., Caeiro, J. R., Sanz-Moreno, V., Aasen, T., Blanco, M. G., Sabio, G., Quindós, M., Rivas, C., Santamaría, D., ... Mayán, M. D. (2025). Cx43 enhances response to BRAF/MEK inhibitors by reducing DNA repair capacity. Nature Communications, 16, Article 6168. Advance online publication. https://doi.org/10.1038/s41467-025-60971-3

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title = "Cx43 enhances response to BRAF/MEK inhibitors by reducing DNA repair capacity",

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.",

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author = "Adri{\'a}n Varela-V{\'a}zquez and Amanda Guiti{\'a}n-Caama{\~n}o and Paula Carpintero-Fern{\'a}ndez and Alexander Carneiro-Figueira and Vanesa {\'A}lvarez and Marta Varela-Eir{\'i}n and Teresa Calleja-Chucl{\'a} and Bravo-L{\'o}pez, \{Susana B.\} and Anxo Vidal and Juan Send{\'o}n-Lago and Mateos, \{Marina Rodriguez-Candela\} and Caeiro, \{Jos{\'e} R.\} and Victoria Sanz-Moreno and Trond Aasen and Blanco, \{Miguel G.\} and Guadalupe Sabio and Mar{\'i}a Quind{\'o}s and Carmen Rivas and David Santamar{\'i}a and Carlos Fernandez-Lozano and Eduardo Fonseca and Pablo Huertas and Berta S{\'a}nchez-Laorden and Constance Alabert and May{\'a}n, \{Mar{\'i}a D.\}",

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doi = "10.1038/s41467-025-60971-3",

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journal = "Nature Communications",

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Varela-Vázquez, A, Guitián-Caamaño, A, Carpintero-Fernández, P, Carneiro-Figueira, A, Álvarez, V, Varela-Eirín, M, Calleja-Chuclá, T, Bravo-López, SB, Vidal, A, Sendón-Lago, J, Mateos, MR-C, Caeiro, JR, Sanz-Moreno, V, Aasen, T, Blanco, MG, Sabio, G, Quindós, M, Rivas, C, Santamaría, D, Fernandez-Lozano, C, Fonseca, E, Huertas, P, Sánchez-Laorden, B, Alabert, C & Mayán, MD 2025, 'Cx43 enhances response to BRAF/MEK inhibitors by reducing DNA repair capacity', Nature Communications, vol. 16, 6168. https://doi.org/10.1038/s41467-025-60971-3

TY - JOUR

T1 - Cx43 enhances response to BRAF/MEK inhibitors by reducing DNA repair capacity

AU - Varela-Vázquez, Adrián

AU - Guitián-Caamaño, Amanda

AU - Carpintero-Fernández, Paula

AU - Carneiro-Figueira, Alexander

AU - Álvarez, Vanesa

AU - Varela-Eirín, Marta

AU - Calleja-Chuclá, Teresa

AU - Bravo-López, Susana B.

AU - Vidal, Anxo

AU - Sendón-Lago, Juan

AU - Mateos, Marina Rodriguez-Candela

AU - Caeiro, José R.

AU - Sanz-Moreno, Victoria

AU - Aasen, Trond

AU - Blanco, Miguel G.

AU - Sabio, Guadalupe

AU - Quindós, María

AU - Rivas, Carmen

AU - Santamaría, David

AU - Fernandez-Lozano, Carlos

AU - Fonseca, Eduardo

AU - Huertas, Pablo

AU - Sánchez-Laorden, Berta

AU - Alabert, Constance

AU - Mayán, María D.

PY - 2025/7/4

Y1 - 2025/7/4

N2 - 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.

AB - 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.

KW - Connexin 43/metabolism

KW - DNA Repair/drug effects

KW - Proto-Oncogene Proteins B-raf/antagonists & inhibitors

KW - Humans

KW - Cell Line, Tumor

KW - Protein Kinase Inhibitors/pharmacology

KW - Animals

KW - DNA Damage/drug effects

KW - Mice

KW - Drug Resistance, Neoplasm/drug effects

KW - Extracellular Vesicles/metabolism

KW - Mutation

KW - Cellular Senescence/drug effects

UR - https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD053555

UR - https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA1225446

U2 - 10.1038/s41467-025-60971-3

DO - 10.1038/s41467-025-60971-3

M3 - Article

C2 - 40615399

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 6168

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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