ATR inhibitor-induced CDK1-SPOP axis destabilizes PD-L1 and enhances cytotoxicity in prostate cancer.

Abstract

PURPOSE\nDespite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICB response in solid tumors in part due to induction of mitotic catastrophe and innate immune activation. Discerning the underlying mechanisms of this DDRi-ICB interaction in a prostate-cancer specific manner is vital to guide novel clinical trials and provide durable clinical responses for men with CRPC.\n\n\nEXPERIMENTAL DESIGN\nWe treated prostate cancer cell lines with potent, specific inhibitors of ATR kinase, as well as with PARP inhibitor, olaparib. We performed analyses of cGAS-STING and DDR signaling in treated cells, and treated a syngeneic androgen-indifferent, prostate cancer model with combined ATR inhibition and anti-PDL1, and performed scRNA-seq analysis in treated tumors.\n\n\nRESULTS\nATRi (BAY1895433) directly repressed ATR-CHK1 signaling, activated CDK1-SPOP axis, leading to destabilization of PD-L1 protein. These effects of ATRi are distinct from those of olaparib, and resulted in a cGAS-STING-initiated, IFN-ß-mediated, autocrine, apoptotic response in CRPC. The combination of ATRi with anti-PDL1 therapy resulted in robust innate immune activation and a synergistic, T-cell dependent therapeutic response in our syngeneic mouse model.\n\n\nCONCLUSIONS\nThis work provides a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade for patients with CRPC. Multiple early phase clinical trials of this combination are underway.