Abstract 5684: PARP inhibitors boost antitumor effects of ADAR1 inhibition regardless of BRCA1 status

Abstract Triple-negative breast cancer (TNBC), characterized by the absence of estrogen and progesterone receptors and HER2, is the most aggressive form of breast cancer. Despite recent advances in treatment, patients with advanced TNBC continue to face the worst prognostic outcomes among all breast cancer subtypes. In this project, we aim to develop new and more effective therapies for advanced TNBC. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), a class of drugs that target the DNA damage repair response, are the first and only targeted therapy approved for patients with advanced or metastatic TNBC. PARPis are best known for inducing synthetic lethality in tumors deficient in homologous recombination (HR) repair proteins like BRCA1/2. Thus, their approval is limited to BRCA1/2-deficient breast cancer. We and others recently demonstrated that PARPis can also trigger anti-tumor immunity by activating the STING-type I interferon signaling axis (PMID: 30540933, 35641483). However, it remains unclear whether the immunomodulatory role of PARPis can be exploited to expand their use in TNBC. In this study, we found that PARP inhibition increased interferon-stimulated gene (ISG) expression in both BRCA1-deficient and BRCA1-proficient breast cancer cells. This finding is significant because previous studies suggest that cancers with elevated ISG expression are highly reliant on the RNA editing enzyme adenosine deaminase 1 (ADAR1) for survival, making them susceptible to ADAR1 inhibition (ADAR1i). To investigate this further, we utilized tumor cell lines derived from genetically engineered mouse models (GEMMs) of TNBC and employed siRNA, shRNA, and small molecule inhibitors against ADAR1. Notably, we demonstrated that combining PARPi with ADAR1i synergistically killed TNBC cells, regardless of their BRCA status. Taken together, our results highlight the potential of combing PARPis with ADAR1i for treating TNBC, including BRCA-proficient tumors. Citation Format: Sophie O'Keefe, Dhillon Parikshak, Marcus Meade, Qiwei Wang. PARP inhibitors boost antitumor effects of ADAR1 inhibition regardless of BRCA1 status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5684.