Synthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma

Ana Portelinha, Mariana Silva Ferreira, Tatiana Erazo, Man Jiang, Zahra Asgari, Elisa Stanchina, Anas Younes () and Hans-Guido Wendel ()
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Ana Portelinha: Memorial Sloan-Kettering Cancer Center
Mariana Silva Ferreira: Memorial Sloan-Kettering Cancer Center
Tatiana Erazo: Department of Medicine Lymphoma Service Memorial Sloan-Kettering Cancer Center
Man Jiang: Memorial Sloan-Kettering Cancer Center
Zahra Asgari: Department of Medicine Lymphoma Service Memorial Sloan-Kettering Cancer Center
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Anas Younes: Department of Medicine Lymphoma Service Memorial Sloan-Kettering Cancer Center
Hans-Guido Wendel: Memorial Sloan-Kettering Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Spontaneous whole genome duplication and the adaptive mutations that disrupt genome integrity checkpoints are infrequent events in B cell lymphomas. This suggests that lymphomas might be vulnerable to therapeutics that acutely trigger genomic instability and polyploidy. Here, we report a therapeutic combination of inhibitors of the Polo-like kinase 4 and BCL-2 that trigger genomic instability and cell death in aggressive lymphomas. The synthetic lethality is selective for tumor cells and spares vital organs. Mechanistically, inhibitors of Polo-like kinase 4 impair centrosome duplication and cause genomic instability. The elimination of polyploid cells largely depends on the pro-apoptotic BAX protein. Consequently, the combination of drugs that induce polyploidy with the BCL-2 inhibitor Venetoclax is highly synergistic and safe against xenograft and PDX models. We show that B cell lymphomas are ill-equipped for acute, therapy-induced polyploidy and that BCL-2 inhibition further enhances the removal of polyploid lymphoma cells.

Date: 2023
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DOI: 10.1038/s41467-023-37216-2

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