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.See related commentary by Savona and Rathmell, p. 831.This article is highlighted in the In This Issue feature, p. 813.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Nechiporuk T,Kurtz SE,Nikolova O,Liu T,Jones CL,D'Alessandro A,Culp-Hill R,d'Almeida A,Joshi SK,Rosenberg M,Tognon CE,Danilov AV,Druker BJ,Chang BH,McWeeney SK,Tyner JWdoi
10.1158/2159-8290.CD-19-0125subject
Has Abstractpub_date
2019-07-01 00:00:00pages
910-925issue
7eissn
2159-8274issn
2159-8290pii
2159-8290.CD-19-0125journal_volume
9pub_type
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