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Review
. 2022 May 6;5(2):380-400.
doi: 10.20517/cdr.2021.125. eCollection 2022.

Venetoclax resistance: mechanistic insights and future strategies

Faustine Ong  1 , Kunhwa Kim  1 , Marina Y Konopleva  1
Affiliations
Review

Venetoclax resistance: mechanistic insights and future strategies

Faustine Ong et al. Cancer Drug Resist. .

Abstract

Acute myeloid leukemia (AML) is historically associated with poor prognosis, especially in older AML patients unfit for intensive chemotherapy. The development of Venetoclax, a potent oral BH3 (BCL-2 homology domain 3) mimetic, has transformed the AML treatment. However, the short duration of response and development of resistance remain major concerns. Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens. In this review, we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies. Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations. Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.

Keywords: Azacitidine; BCL2 protein; Decitabine; Venetoclax; acute myeloid leukemia; human; hypomethylating agents; resistance.

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Conflict of interest statement

Marina Konopleva: Consultant for AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, KisoJi, Janssen; serves as advisory board member for Stemline Therapeutics, F. Hoffman La-Roche, Janssen; holds shares from Reata Pharmaceuticals; honoraria from Forty-Seven and F. Hoffman La-Roche; research funding from AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Stemline Therapeutics, Ablynx, Agios, Ascentage, Astra Zeneca, Rafael Pharmaceutical, Sanofi, and Forty-Seven.

Figures

Figure 1
Figure 1
Binding of BH3 mimetic, Venetoclax to BCL-2 anti-apoptotic protein releases bound BH3-only protein, subsequently allowing interaction between BH3-only protein and BAK/BAX. Upregulation of MCL-1, BCL-xL, and BCL2-A1 confers Venetoclax resistance by sequestration of BH3 only proteins, preventing them from interacting with BAK/BAX and avoidance of apoptosis[35-40].
Figure 2
Figure 2
FLT3-ITD mutation causes an increased level of BCL-xL and MCL-1 via activation of downstream PI3K-AKT, RAS-MAPK, and STAT5 pathways. AKT and ERK promoted inhibitory phosphorylation of GSK3, leading to a reduction of MCL1 ubiquitination and degradation. In addition to upregulation of MCL-1 and BCL-xL, STAT5 also increases MCL-1 indirectly through AKT activation. In summary, FLT3-ITD mutation confers Venetoclax resistance by upregulation of BCL-xL and MCL-1[48-53].
Figure 3
Figure 3
Both KRAS and PTPN11 mutations confer Venetoclax resistance. KRAS mutation causes upregulation of MCL-1 and BCL2A1, while PTPN11 mutation causes upregulation of MCL-1 and BCL-xL. KRAS mutation also downregulates BCL-2 and BAX[37].
See this image and copyright information in PMC

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