TY - JOUR T1 - PARP and PI3K inhibitor combination therapy eradicates c-MYC-driven murine prostate cancers via cGAS/STING pathway activation within tumor-associated macrophages JF - bioRxiv DO - 10.1101/2020.07.17.198598 SP - 2020.07.17.198598 AU - Priyanka Dutta Gupta AU - Kiranj Chaudagar AU - Sweta Sharma-Saha AU - Kaela Bynoe AU - Lea Maillat AU - Brian Heiss AU - Walter M Stadler AU - Akash Patnaik Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/18/2020.07.17.198598.abstract N2 - The majority of metastatic, castrate-resistant prostate cancer (mCRPC) patients are de novo resistant to immune checkpoint blockade (ICB), so therapeutic strategies to enhance immune-responsiveness are urgently needed. Here 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 murine models, respectively, which demonstrated lack of efficacy. In contrast, 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. These data demonstrate that PARPi/PI3Ki combination triggers macrophage STING-mediated anti-cancer innate immunity, which is sufficient to induce tumor regression in ICB-refractory c-myc-driven prostate cancer.STATEMENT OF SIGNIFICANCE Co-targeting of PARP and PI3K signaling pathways activates c-GAS/STING pathway within tumor-associated macrophages, thereby enhancing T cell recruitment/activation and cancer clearance in c-myc-driven murine prostate cancer models. PARPi/PI3Ki combination therapy could markedly increase the fraction of mCRPC patients responsive to ICB, independent of germline or tumor homologous recombination status.Competing Interest StatementDr. Patnaik has received research support from Bristol Myers Squibb. In addition, Drs. Patnaik and Stadler have received clinical trial funding support from both Clovis Oncology and Bristol Myers Squibb. ER -