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 signaling 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. In this study, 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 is associated with a temporal downregulation of replisome proteins in Rb-proficient but not in Rb-deficient 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): Although upfront combined inhibition of CDK4/6 and PARP1 had no antitumor effect, their sequential use adding PARPi upon CDK4/6i withdrawal and cell-cycle reentry 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 patients with advanced prostate cancer and open avenues for repurposing CDK4/6i therapy in mPC.