Abstract IA024: Targeting E3 ubiquitin ligases for precision oncology: Functional genomics identifies an ovarian cancer specific dependence on CRL4

Abstract Precision oncology approaches seek to identify and exploit tumor specific drug sensitivities. In tumors such as lung cancer, breast cancer, and melanoma, which harbor highly recurrent mutations, genomic based approaches have led to the development of targeted inhibitors (e.g. EGFR, BRAF, PI3K, and KRAS inhibitors). Unfortunately, this paradigm falls short in the contexts like ovarian cancer where the diversity of oncogenic alterations necessitate alternative approaches for the identification of tumor specific vulnerabilities. E3 ubiquitin ligases function to direct selective protein degradation, controlling numerous biological pathways and directly impacting many disease states including cancer. There are multiple features of E3 enzymes that make them idealized targets for precision oncology. First, they are highly specific in their recognition of substrate proteins. Second, they have distinct expression patterns across tissue and cell types. Third, their substrate recognition includes redundancies. Fourth, and because of the these, different cell types show distinct patterns of dependence upon individual E3 ligases. This suggests that these features have evolved so that the requirement for individual E3 ligases varies across tissue and tumor types, as differences in expression patterns and functional redundancies alter the requirements for individual E3 ligases in specific contexts. These features may allow oncologists to specifically treat cancers by targeting individual E3 ligases without inducing the broad toxicity seen with agents that lack tumor specificity. Running our functional genomics pipeline we observed an ovarian cancer-specific sensitivity to Cullin-4 RING E3 ubiquitin ligase (CRL4) inhibitors. Reflex RNA-sequencing demonstrated that CRL4 inhibition negatively regulates core gene signatures known to drive growth in ovarian cancer. Performing proteomic and transcriptomic profiling to identify ways to improve the antitumor effects of CRL4 inhibition in ovarian cancer models we observed increased activation of the mitogen-activated protein kinase (MAPK) signaling cascade suggesting that survival signaling is induced in response to CRL4 inhibition. These observations were concordant with the results of the combination drug screens in seven ovarian cancer cell lines that showed CRL4 inhibition cooperates with MEK inhibition. Together, these data demonstrate the prospective utility of functional modeling pipelines for therapeutic development and underscore the potential utility of targeting individual E3 ligases in precision oncology. Citation Format: Benjamin D Hopkins. Targeting E3 ubiquitin ligases for precision oncology: Functional genomics identifies an ovarian cancer specific dependence on CRL4 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr IA024.