Abstract 5890: ZNF451 and Doxorubicin Resistance

Abstract Precision medicine most often utilizes mutations in patient selection, however targetable mutations are exceedingly rare in high-grade serous ovarian cancer (OV). Aneuploidy and chromosome instability are major contributors to such genomic changes in OV. Genes are pervasively disrupted by copy-number alterations: 39% of all genes in the median solid tumor of all cancer types, and 67% in OV. A common second-line OV chemotherapeutic is peggylated-liposomal doxorubicin, a topoisomerase-II poison. To address which genes in OV contribute to doxorubicin sensitivity and resistance, we performed a CRISPR-Cas9 screen on 19,114 human genes in the presence or absence of doxorubicin. Positive control genes involved in drug-efflux and DNA repair were significant hits. The gene with both the highest significance and greatest magnitude of doxorubicin sensitization upon knockout was the E3 SUMO2/3 ligase ZNF451. ZNF451 exhibits a copy-number loss in 14% of patients and corresponds to ZNF451 protein reduction. ZNF451 is an attractive target for future combination therapies with doxorubicin to induce conditional lethality. ZNF451 may be valuable to study as a prognostic biomarker for topoisomerase-II inhibitor chemotherapy. Citation Format: Amy Rees, Alexandra Blackman, Della Evans, Joe Delaney. ZNF451 and doxorubicin resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5890.