AKT1 Is Required for a Complete Palbociclib-Induced Senescence Phenotype in BRAF-V600E-Driven Human Melanoma

Simple Summary One of the hallmarks of cancer is increased cellular proliferation; therefore, many therapeutic strategies aim at arresting cellular division. Several chemotherapeutic drugs, including CDK4/6 inhibitors (CDK4/6i), result in cellular senescence, in which cells irreversibly stop proliferating and undergo many changes in function. However, some forms of senescence result in the release of factors that can worsen cancer progression. The AKT family of genes are a major regulator of cellular proliferation and senescence; therefore, we sought to study each of the three AKT isoforms in the senescence response to CDK4/6i. We found that only AKT1 is required for a full senescence phenotype induced by CDK4/6i, which works through the NF-kappa B pathway. This study suggests that targeting AKT1 in combination with CDK4/6i represents a therapeutic strategy in which cellular senescence can be achieved without the release of pro-cancer factors. Cellular senescence is a carefully regulated process of proliferative arrest accompanied by functional and morphologic changes. Senescence allows damaged cells to avoid neoplastic proliferation; however, the induction of the senescence-associated secretory phenotype (SASP) can promote tumor growth. The complexity of senescence may limit the efficacy of anti-neoplastic agents, such as CDK4/6 inhibitors (Cdk4/6i), that induce a senescence-like state in tumor cells. The AKT kinase family, which contains three isoforms that play both unique and redundant roles in cancer progression, is commonly hyperactive in many cancers including melanoma and has been implicated in the regulation of senescence. To interrogate the role of AKT isoforms in Cdk4/6i-induced cellular senescence, we generated isoform-specific AKT knockout human melanoma cell lines. We found that the CDK4/6i Palbociclib induced a form of senescence in these cells that was dependent on AKT1. We then evaluated the activity of the cGAS-STING pathway, recently implicated in cellular senescence, finding that cGAS-STING function was dependent on AKT1, and pharmacologic inhibition of cGAS had little effect on senescence. However, we found SASP factors to require NF-kappa B function, in part dependent on a stimulatory phosphorylation of IKK alpha by AKT1. In summary, we provide the first evidence of a novel, isoform-specific role for AKT1 in therapy-induced senescence in human melanoma cells acting through NF-kappa B but independent of cGAS.

Automated summary

Cellular senescence is a critical process regulated by AKT isoforms and NF-kappa B pathway, and plays a role in cancer progression. This study demonstrates that AKT1 is essential for CDK4/6 inhibitor-induced senescence and its effect is independent of cGAS. Targeting AKT1 in combination with CDK4/6 inhibitors could be a potential therapeutic strategy to induce senescence without promoting cancer progression.