Abstract 1685: PARP/PI3K inhibitor combination therapy eradicates c-MYC-driven murine prostate cancers via cGAS/STING pathway activation within tumor-associated macrophages

Abstract

Abstract There has been a resurgent interest in prostate cancer (PC) immunotherapy, partly based on the profound and durable clinical responses to immune checkpoint blockade (ICB) antibodies targeting CTLA-4 and PD-1/PD-L1 in multiple other cancers, and partly due to emergence of resistance to various androgen receptor-based therapies. However, only approximately 10% of metastatic castrate-resistant prostate cancer (mCRPC) patients respond to ICB. Therefore, therapeutic strategies to enhance immune-responsiveness are urgently needed. Prior studies have demonstrated that PARP inhibitors (PARPi) can activate the innate immune cGAS/STING pathway in BRCA-deficient triple-negative breast and ovarian cancer models, resulting in sensitization of these tumors to ICB. Furthermore, we have recently demonstrated that PARPi can elicit DNA damage in c-myc-driven HR-proficient PC. We therefore hypothesized that c-GAS/STING pathway activation should occur following PARP inhibitor (PARPi) therapy insomuch as these agents generate DNA DSBs, regardless of underlying DNA repair mutations, thereby resulting in sensitization to ICB. To test the above hypothesis, we performed a co-clinical trial of PARP inhibitor (PARPi) in combination with PD-1 or PDL-1 antibody in genomically unselected mCRPC patients or homologous-recombination proficient c-myc driven murine models, respectively, which demonstrated lack of efficacy. Probing more deeply into this paradox, we found that failed STING pathway activation within the myeloid compartment was responsible for this therapeutic resistance to PARPi/ICB combination therapy. Specifically, PI3K activity was preventing STING pathway activation in tumor-associated macrophages (TAMs), and PI3K inhibition plus PARP inhibition led to significantly enhanced ICB responsiveness. Critically, we observed that PARPi in combination with PI3K inhibitor (PI3Ki) induced tumor regression via macrophage STING-dependent innate immune activation in vivo, and enhanced T-cell infiltration/activation in c-myc driven murine prostate cancer models, which was augmented by PD-L1 blockade. Ex vivo mechanistic studies revealed that PARPi-induced DNA double strand break-associated microvesicles released from tumor cells, coupled with PI3Ki mediated c-GAS de-repression, were both required for macrophage cGAS/STING pathway activation. In summary, co-targeting of PARP and PI3K signaling pathways activates c-GAS/STING pathway within TAMs, thereby enhancing T cell recruitment/activation and cancer clearance in c-myc-driven murine prostate cancer models. From a translational standpoint, these data demonstrate that PARPi/PI3Ki combination therapy could markedly increase the fraction of mCRPC patients responsive to ICB, independent of germline or tumor homologous recombination status. Citation Format: Priyanka Gupta, Kiranj Chaudagar, Sweta Sharma-Saha, Kaela Bynoe, Lea Maillat, Brian Heiss, KaHo Leung, Yamuna Krishnan, Walter Stadler, Akash Patnaik. PARP/PI3K inhibitor combination therapy eradicates c-MYC-driven murine prostate cancers via cGAS/STING pathway activation within tumor-associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1685.