Dual Role of Cx43 in Enhancing CDK4/6 Inhibitor Response and Promoting the Elimination of Therapy-Induced Senescent Tumor Cells

Upregulation of connexin 43 (Cx43) in luminal (ER/HER2-) breast cancer potentiates CDK4/6 inhibitor therapy by enhancing senescence and sensitizing therapy-induced senescent cells to Navitoclax.

• Why it matters: CDK4/6 inhibitors plus endocrine therapy can induce senescence, but limited efficacy and resistance persist because accumulated senescent tumor cells are not fully eliminated.
• What they did: The study identifies Cx43 as a novel target that enhances CDK4/6 inhibitor effects, reinforcing G1 arrest via transcriptional downregulation of E2F targets (including CDK4 and CDK6) and interaction with p21/p27, while reshaping the SASP profile.
• The result: Cx43-associated senescent phenotypes sensitize CDK4/6i-treated tumor cells to the senolytic agent Navitoclax, supporting a triple-drug strategy (CDK4/6i, Cx43 delivery, Navitoclax) to overcome CDK4/6i resistance in ER/HER2- breast cancer.