Abstract LB182: Targeting arginine methylation for improved therapy in triple negative breast cancer

Abstract

Abstract Since the discovery of DNA repair deficiency as risk factors for breast cancer, our knowledge of their function in maintaining human genomic integrity and a normal biological function has greatly advanced, ultimately culminating in development of PARP inhibitors that can specifically target patients who harbor these mutations. However, to date PARP inhibitors have demonstrated only modest clinical success as monotherapy in triple-negative breast cancer. In addition, conventional therapies are often coupled with severe toxicity. Therefore, there is a dire need to develop more effective combination therapies. Although there are many existing tools to predict possible actionable targets, it remains challenging to effectively and systematically identify drug combinations for better breast cancer therapeutics. This is because most tumors carry multiple genetic alterations that cannot be suppressed with mono-therapies; and diverse confounding factors such as intra-tumor and inter-tumor heterogeneity exist across patient populations. Our preliminary proteomics study has revealed a new protein mark called arginine methylation as a novel target for breast cancer. We found that inhibition of arginine methylation can sensitize cancer cells for PARP inhibition treatment. We further assessed and validated this actionable and synergistic drug combination in patient-derived xenograft models. Together, our novel target combinations discovered here may serve as important biomarkers to help develop more effective combination therapy. Furthermore, our results help uncover patient-specific signaling mechanisms, a critical step towards precision medicine in breast cancer therapy, which is a benefit and potential long-term outcome. Citation Format: Yang Li, Daniel J. McGrail, Sharad Awasthi, S. Stephen Yi, Mark T. Bedford, Nidhi Sahni. Targeting arginine methylation for improved therapy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB182.