The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells

Tamilla Nechiporuk, Stephen E. Kurtz, Olga Nikolova, Tingting Liu, Courtney L. Jones, Angelo D’alessandro, Rachel Culp-Hill, Amanda D’almeida, Sunil K. Joshi, Mara Rosenberg, Cristina E. Tognon, Alexey V. Danilov, Brian J. Druker, Bill H. Chang, Shannon K. McWeeney, Jeffrey W. Tyner

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

To study mechanisms underlying resistance to the BCL2 inhibitor venetoclax in acute myeloid leukemia (AML), we used a genome-wide CRISPR/Cas9 screen to identify gene knockouts resulting in drug resistance. We validated TP53, BAX, and PMAIP1 as genes whose inactivation results in venetoclax resistance in AML cell lines. Resistance to venetoclax resulted from an inability to execute apoptosis driven by BAX loss, decreased expression of BCL2, and/or reliance on alternative BCL2 family members such as BCL2L1. The resistance was accompanied by changes in mitochondrial homeostasis and cellular metabolism. Evaluation of TP53 knockout cells for sensitivities to a panel of small-molecule inhibitors revealed a gain of sensitivity to TRK inhibitors. We relate these observations to patient drug responses and gene expression in the Beat AML dataset. Our results implicate TP53, the apoptotic network, and mitochondrial functionality as drivers of venetoclax response in AML and suggest strategies to overcome resistance. SIGNIFICANCE: AML is challenging to treat due to its heterogeneity, and single-agent therapies have universally failed, prompting a need for innovative drug combinations. We used a genetic approach to identify genes whose inactivation contributes to drug resistance as a means of forming preferred drug combinations to improve AML treatment.

Original languageEnglish (US)
Pages (from-to)910-925
Number of pages16
JournalCancer discovery
Volume9
Issue number7
DOIs
StatePublished - Jul 2019

ASJC Scopus subject areas

  • Oncology

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    Nechiporuk, T., Kurtz, S. E., Nikolova, O., Liu, T., Jones, C. L., D’alessandro, A., Culp-Hill, R., D’almeida, A., Joshi, S. K., Rosenberg, M., Tognon, C. E., Danilov, A. V., Druker, B. J., Chang, B. H., McWeeney, S. K., & Tyner, J. W. (2019). The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells. Cancer discovery, 9(7), 910-925. https://doi.org/10.1158/2159-8290.CD-19-0125