Abstract 4305: Targeting the exonuclease domain of POLE to induce synthetic lethality in highly aneuploidic tumor cells

Abstract Aneuploidy is a hallmark of cancer evolution, it is associated with fast disease progression and drug resistance across many tumor types. The underlying molecular aberration that causes aneuploidy remains largely unknown. Currently, there are no established therapeutics for tumors with high levels of aneuploidy. We propose that inhibition of the exonuclease domain of the DNA polymerase, POLE, could induce synthetic lethality in tumor cells with high levels of aneuploidy. We observed that loss of function mutations in the exonuclease domain of POLE are mutually exclusive with high levels of aneuploidy in the Foundation Medicine database, the Cancer Genome Atlas (TCGA) as well as the cancer Dependency Map (DepMap). Our analysis and statistical modeling showed that the number and unique spectrum of mutations induced by loss of POLE’s exonuclease activity have a high probability of hitting an essential gene with hemizygous loss in aneuploidic tumor cells, therefore leading to a synthetic lethality phenotype. Experimentally, we showed that specific inhibition of the exonuclease domain through genetic mutations can cause strong cellular fitness effects in highly aneuploidic cell lines. In summary, our data suggest that a specific inhibitor targeting the exonuclease domain of POLE might bring therapeutic benefits to patients with highly aneuploidic tumors. Citation Format: Meng He, Eun Jung Kim, Yangmeng Wang, Alejandro Chibly, Kristel Dorighi. Targeting the exonuclease domain of POLE to induce synthetic lethality in highly aneuploidic tumor cells [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 4305.