Abstract 359: Pharmacologically induced polyploidy triggers BCL2 dependence in lymphomas

Abstract

Abstract Spontaneous whole genome duplication (WGD) and the adaptive mutations that disrupt cell death and proliferation checkpoints are infrequent events in aggressive B cell lymphomas. This indicates that lymphomas may be especially sensitive to therapeutics that trigger genomic instability. Here, we report the powerful therapeutic combination of Polo-like kinase 4 (PLK4) and BCL2 inhibitors for aggressive lymphomas. Mechanistically, the PLK4 inhibitor CFI-400945 impairs centrosome duplication leading to genomic instability and tetraploidy (4n) in lymphoma cells. Elimination of polyploid lymphoma cells is mediated by the pro-apoptotic BAX protein resulting in increased BCL2 dependence for cell survival. The selective BCL2 inhibitor, venetoclax, acts in a synthetic lethal manner with PLK4 inhibition in both CFI-400945 sensitive and in CFI-400945 resistant lymphomas. As PLK4 is dispensable in non-proliferating cells, synthetic lethality is preferentially observed in tumor cells, while sparing vital organs. Hence, B cell lymphomas are ill-prepared for the rapid, pharmacologic induction of polyploidy resulting in a synthetic and tumor-specific dependency on BCL2. Citation Format: Ana Portelinha, Mariana da Silva Ferreira, Tatiana Erazo, Zahra Asgari, Elisa de Stanchina, Anas Younes, Hans-Guido Wendel. Pharmacologically induced polyploidy triggers BCL2 dependence in lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 359.