Dual Role of Cx43 in Enhancing CDK4/6 Inhibitor Response and Promoting the Elimination of Therapy-Induced Senescent Tumor Cells
- 1CellCOM Research Group. Center for Research in Nanomaterials and Biomedicine (CINBIO) and Institute of Biomedical Research of Ourense-Pontevedra-Vigo (IBI), Uni
Abstract
Breast cancer has become the most prevalent malignancy worldwide. A key clinical advance has been the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), that in combination with endocrine therapy has been a major advance for the treatment of luminal (ER/HER2-) breast cancer. CDK4/6i induce cell cycle arrest in G1 and cellular senescence improving clinical outputs. However, limited efficacy and therapeutic resistance remain major challenges due to incomplete effects or the failure to eliminate the accumulated tumor senescent cells. Here, we identify connexin 43 (Cx43), a membrane channel protein involved in cell-to-cell communication, identified as a novel target in luminal breast cancer that potentiates the effects of CDK4/6 inhibitors. We found that Cx43 not only reduces tumor cell proliferation by enhancing senescence but also reshapes the Senescence-Associated Secretory Phenotype (SASP) profile. We also demonstrate that, in combination with CDK4/6i, Cx43 reinforces G1 arrest via transcriptional downregulation of E2F targets including CDK4 and CDK6, and through interaction with p21/p27, deepens the senescent state. Importantly, the Cx43-associated senescent phenotype sensitizes tumor cells accumulated under CDK4/6i treatment to the senolytic agent Navitoclax. Our results demonstrate that upregulation of Cx43 in breast cancer reduces proliferation and enhances the clearance of therapy-induced senescent cells. The triple-drug strategy comprising CDK4/6i, Cx43 delivery, and a senolytic drug such as Navitoclax holds great promise for overcoming CDK4/6i resistance and improving clinical outcomes in ER/HER2- breast cancer and may also be applicable to other cancer types that respond to CDK4/6i or other pro-senescence antitumoral drugs.
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BibTeX
@misc{carpinterofernandez2026dual,
title = {{Dual Role of Cx43 in Enhancing CDK4/6 Inhibitor Response and Promoting the Elimination of Therapy-Induced Senescent Tumor Cells}},
author = {P. Carpintero-Fernandez and M. Barturen-Gomez and V. Alvarez and A. Carneiro-Figueira and S. Mazumdar and L. De Chiara and A. Garcia-Yuste and M. Soler and S. Bravo and J. Mosquera and B. Acea and C. Fernandez-Lozano and M. M. Caffarel and C. Alabert and M. D. Mayan},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761820},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761820v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Dual Role of Cx43 in Enhancing CDK4/6 Inhibitor Response and Promoting the Elimination of Therapy-Induced Senescent Tumor Cells
AU - P. Carpintero-Fernandez
AU - M. Barturen-Gomez
AU - V. Alvarez
AU - A. Carneiro-Figueira
AU - S. Mazumdar
AU - L. De Chiara
AU - A. Garcia-Yuste
AU - M. Soler
AU - S. Bravo
AU - J. Mosquera
AU - B. Acea
AU - C. Fernandez-Lozano
AU - M. M. Caffarel
AU - C. Alabert
AU - M. D. Mayan
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761820
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761820v1
AB - Breast cancer has become the most prevalent malignancy worldwide. A key clinical advance has been the introduction of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), that in combination with endocrine therapy has been a major advance for the treatment of luminal (ER/HER2-) breast cancer. CDK4/6i induce cell cycle arrest in G1 and cellular senescence improving clinical outputs. However, limited efficacy and therapeutic resistance remain major challenges due to incomplete effects or the failure to eliminate the accumulated tumor senescent cells. Here, we identify connexin 43 (Cx43), a membrane channel protein involved in cell-to-cell communication, identified as a novel target in luminal breast cancer that potentiates the effects of CDK4/6 inhibitors. We found that Cx43 not only reduces tumor cell proliferation by enhancing senescence but also reshapes the Senescence-Associated Secretory Phenotype (SASP) profile. We also demonstrate that, in combination with CDK4/6i, Cx43 reinforces G1 arrest via transcriptional downregulation of E2F targets including CDK4 and CDK6, and through interaction with p21/p27, deepens the senescent state. Importantly, the Cx43-associated senescent phenotype sensitizes tumor cells accumulated under CDK4/6i treatment to the senolytic agent Navitoclax. Our results demonstrate that upregulation of Cx43 in breast cancer reduces proliferation and enhances the clearance of therapy-induced senescent cells. The triple-drug strategy comprising CDK4/6i, Cx43 delivery, and a senolytic drug such as Navitoclax holds great promise for overcoming CDK4/6i resistance and improving clinical outcomes in ER/HER2- breast cancer and may also be applicable to other cancer types that respond to CDK4/6i or other pro-senescence antitumoral drugs.
ER -