Abstract LB427: UBA1 blockade induces homologous recombination deficiency and is synthetic lethal with PARP inhibition

Abstract Therapeutic strategies targeting DNA damage have revolutionized cancer treatment, yet their efficacy often comes at the cost of substantial adverse effects. The emergence of poly-ADP-ribose polymerase (PARP) inhibition as a targeted approach to disrupt DNA repair in tumors deficient in homologous recombination (HR) has shown promise. However, the limited response of most cancers to PARP inhibitors has posed a significant challenge. This study employs a genome-wide CRISPR knockout functional genomics screen, revealing that depletion of ubiquitin-activating enzyme E1 (UBA1) enhances sensitivity to PARP inhibition in HR-proficient ovarian cancer cells. Validation across different ovarian and breast cancer cell lineages, utilizing cell line and organoid models, establishes that pharmacological inhibition of UBA1, a pivotal player in ubiquitination, sensitizes cells to PARP inhibition and other DNA damaging therapies. In vivo experiments combining PARP and UBA1 inhibition demonstrate not only tolerability but also significant extension of survival in patient-derived xenografts compared to individual therapies. Mechanistic studies uncover that UBA1 inhibition not only impedes HR repair, sensitizing cells to PARP inhibition, but also induces widespread increases in PARylation, subsequently targeted by PARP inhibition. These findings underscore the multifaceted pathways through which UBA1 inhibition potentiates the efficacy of PARP inhibition. The demonstrated tolerability and substantial therapeutic gains establish the combined approach as a promising strategy to maximize the benefits of PARP inhibition in cancer therapy. Citation Format: Sharad Awasthi, Daniel J. McGrail, S. Stephen Yi, Nidhi Sahni. UBA1 blockade induces homologous recombination deficiency and is synthetic lethal with PARP inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB427.