Harnessing senolytics and PARP inhibition to expand the antitumor activity of CDK4/6 inhibitors in prostate cancer.

Metastatic prostate cancer (mPC) is a lethal disease; most therapeutic options focus on androgen receptor (AR) signalling inhibition, but resistance eventually arises. Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have shown antitumor efficacy in mPC preclinical models, but their efficacy in mPC clinical trials has been limited. We hypothesize that novel combination therapies designed leveraging mPC adaptation to CDK4/6i could lead to increased and sustained antitumor effect. Herein, we demonstrate in a range of in vitro and in vivo prostate cancer models, including patient-derived xenografts, that prostate cancer cells adopt a senescent phenotype upon CDK4/6 inhibition that can be selectively targeted using senolytic compounds. Notably, interrupting CDK4/6 inhibition in intermittent drug schedules prompts a rapid bypass of the senescent phenotype that associates with a temporal downregulation of replisome proteins in RB1 proficient, but not in RB1 KO models, leading to DNA damage accumulation and replication stress following treatment withdrawal. This effect opens a window of opportunity for treatment with PARP inhibitors (PARPi): while upfront combined inhibition of CDK4/6 and PARP1 has no antitumor effect, their sequential use adding PARPi upon CDK4/6i withdrawal and cell cycle re-entry results in major antitumor activity. Our findings underscore the potential of CDK4/6i in prostate cancer therapy, particularly when administered under biology-driven sequential use of senolytic therapy or PARPi. Such strategic interventions hold promise in overcoming resistance and enhancing treatment outcomes for advanced prostate cancer patients and open avenues for repurposing CDK4/6i therapy in mPC.