Abstract 1133: Novobiocin-mediated polymerase theta inhibition induces cGAS/STING pathway activation and T-cell infiltration in BRCA-associated cancers

Abstract

Abstract Recently developed inhibitors of polymerase theta have demonstrated synthetic lethality in pre-clinical tumor models of BRCA-associated cancers. Given that other DNA damage repair inhibitor therapies, including PARP inhibitors, induce changes in the tumor immune microenvironment, we asked whether polymerase theta inhibition would also alter the tumor microenvironment in BRCA-associated cancers. We have demonstrated that novobiocin, a first-in-class inhibitor of the polymerase theta ATPase domain, induces both innate and adaptive immune responses through activation of the cGAS/STING pathway in BRCA-deficient tumor cells. Novobiocin-mediated polymerase theta inhibition generates micronuclei, activating the cGAS/STING pathway in both BRCA1-deficient MDA-MB-436 triple-negative breast cancer and BRCA2-deficient CAPAN1 pancreatic cancer models in vitro. Activation of the STING pathway upregulated the expression of interferon response genes, which was abrogated upon siRNA-mediated STING depletion. As an adaptive response, novobiocin also increased expression of PD-L1 in BRCA-deficient tumor cells. These effects were not observed in isogenic cell lines in which wild-type BRCA expression was corrected by add-back. Using a genetically engineered syngeneic mouse model of BRCA1-deficient breast cancer, we confirmed novobiocin-mediated activation of the cGAS/STING pathway in vivo, resulting in the induction of pro-inflammatory signaling and ultimately robust CD8+ T-cell infiltration and activation. Taken together, our findings demonstrate that novobiocin-mediated polymerase theta inhibition induces local and systemic immune responses in a cGAS/STING-dependent manner and provide a rationale for combining polymerase theta inhibition with immunotherapies for the treatment of BRCA-associated cancers. Citation Format: Jeffrey Patterson-Fortin, Heta Jadhav, Tin Phan, Alan D'Andrea, Geoffrey I. Shapiro. Novobiocin-mediated polymerase theta inhibition induces cGAS/STING pathway activation and T-cell infiltration in BRCA-associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1133.