Abstract IA015: Identifying and targeting synthetic lethalities of aneuploid (cancer) cells

Aneuploidy, an imbalanced number of chromosomes or chromosome arms, is a genetic hallmark of cancer cells, yet aneuploidy remains a biological enigma and a missed opportunity for cancer therapy. Aneuploid cells must cope with several types of cellular stresses, potentially creating synthetic lethalities that can be used to target aneuploid cancer cells. Here, I will describe our efforts to identify synthetic lethalities of the aneuploid state (in contrast to synthetic lethalities of specific recurrent aneuploidies. Specifically, I will focus on three recent unpublished studies, where we report that: (1) Aneuploid cells are preferentially sensitive to perturbation of the spindle assembly checkpoint (SAC) and its regulator KIF18A; the expression and activity of CDC20 determine the sensitivity to SAC inhibition. (2) Aneuploid cells depend on MAPK signaling for overcoming aneuploidy-induced DNA damage; targeting MAPK signaling can sensitize aneuploid cells to DNA damage inducing agents and to PARP inhibitors. (3) Aneuploid cells depend on RNA and protein degradation mechanisms to attenuate the cellular consequence of extra chromosomes; this renders aneuploid cells more sensitive to inhibition of nonsense-mediate decay, miRNA-mediated gene silencing, and the proteasome complex. Citation Format: Uri Ben-David. Identifying and targeting synthetic lethalities of aneuploid (cancer) cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA015.