Senolytic Interventions Enhance the Anti-metastatic Activity of Chemotherapy in Prostate Cancer

Abstract Cellular senescence is a common outcome of cytostatic and cytotoxic cancer therapies. While in some contexts therapy-induced senescence can drive tumor growth suppression and anti-tumor immunity through the senescence-associated secretory phenotype (SASP), in others it can promote metastatic progression and immune suppression. A systematic interrogation of the impact of different classes of therapy on heterogeneous senescent phenotypes is required to effectively apply these drugs in specific cancer contexts and to rationally design combination treatments. Using genetically-defined human and murine prostate cancer cell lines, we found that many classes of cancer therapeutics, including chemotherapies and targeted Aurora kinase and CDK inhibitors, could induce cellular senescence, with DNA-damaging agents mediating the most robust growth arrest and SASP. The SASP produced by chemotherapy-induced senescence, particularly with docetaxel, contained not only inflammatory factors that influence immune responses, but also ECM remodeling factors that facilitate tumor cell dissemination. Though docetaxel treatment could induce senescence and reduce tumor growth in syngeneic prostate cancer mouse models, it was not sufficient to activate anti-tumor immunity or slow metastatic dissemination. Senolytic therapies targeting the pro-survival BCL2 and IAP pathways upregulated after docetaxel-induced senescence effectively killed senescent tumor cells through multiple cell death pathways, remodeling the inflammatory SASP to repolarize myeloid phenotypes and potentiate CD8+ T cell activation to further block tumor growth and suppress metastasis. These results suggest that senolytic agents can enhance the immunogenicity and anti-metastatic potential of chemotherapy used for treating advanced prostate cancer patients.