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

   


Authors: Portelinha, A.; da Silva Ferreira, M.; Erazo, T.; Jiang, M.; Asgari, Z.; de Stanchina, E.; Younes, A.; Wendel, H. G.
Article Title: Synthetic lethality of drug-induced polyploidy and BCL-2 inhibition in lymphoma
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. © 2023. The Author(s).
Keywords: genetics; metabolism; protein bcl 2; apoptosis; cell line, tumor; b cell lymphoma; lymphoma, b-cell; genomic instability; tumor cell line; proto-oncogene proteins c-bcl-2; polyploidy; humans; human; lethal mutation; synthetic lethal mutations
Journal Title: Nature Communications
Volume: 14
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2023-03-18
Start Page: 1522
Language: English
DOI: 10.1038/s41467-023-37216-2
PUBMED: 36934096
PROVIDER: scopus
PMCID: PMC10024740
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85150666590&doi=10.1038%2fs41467-023-37216-2&partnerID=40&md5=542c789d7ccb2714dc41c348c77e7618
Notes: Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Hans-Guido Wendel -- Source: Scopus
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MSK Authors
  1. Hans Guido Wendel
    102 Wendel
  2. Elisa De Stanchina
    349 De Stanchina
  3. Man Jiang
    20 Jiang
  4. Zahra Asgari
    11 Asgari
  5. Anas Younes
    320 Younes
  6. Ana Cadete Portelinha
    6 Cadete Portelinha
  7. Ingrid Tatiana Erazo Andrade
    10 Erazo Andrade
  8. Mariana Da Silva Ferreira
    6 Da Silva Ferreira
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