ArticleMolecular cancer therapeutics2022
Maximal Activation of Apoptosis Signaling by Cotargeting Antiapoptotic Proteins in BH3 Mimetic-Resistant AML and AML Stem Cells.
Article in Molecular cancer therapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Article
- Acid ceramidase controls proteasome inhibitor resistance and is a novel therapeutic target for the treatment of relapsed/refractory multiple myeloma.Haematologica · 2025Article
- Unraveling Venetoclax Resistance: Navigating the Future of HMA/Venetoclax-Refractory AML in the Molecular Era.Cancers · 2025Review
- Molecular mechanisms and therapeutic strategies in overcoming chemotherapy resistance in cancer.Molecular biomedicine · 2025Review
- Article
- Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.Leukemia · 2024Article
- Venetoclax Resistance in Acute Myeloid Leukemia.Cancers · 2024Review
- Investigating resistance to 5-Azacytidine and Venetoclax in PDX models of MDS/AML.Frontiers in oncology · 2024Article
- Article
- Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics.Blood cancer journal · 2023Article
- Dual mTORC1/2 Inhibition Synergistically Enhances AML Cell Death in Combination with the BCL2 Antagonist Venetoclax.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- The Growing Role of the BH3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia.Mediterranean journal of hematology and infectious diseases · 2022Review
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
MCL-1 is known to play a major role in resistance to BCL-2 inhibition, but the contribution of other BCL-2 family proteins has not been fully explored. We, here, demonstrate the ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant acute myelogenous leukemia (AML). Like cells with acquired resistance to venetoclax, cells with acquired resistance to AMG176 express increased MCL-1. Both cells with acquired resistance to venetoclax and to AMG176 express increased levels of BCL-2 and BCL-2A1, decreased BAX, and/or altered levels of other BCL-2 proteins. Cotargeting BCL-2 and MCL-1 was highly synergistic in AML cell lines with intrinsic or acquired resistance to BH3 mimetics or engineered to genetically overexpress BCL-2 or BCL-2A1 or downregulate BAX. The combination effectively eliminated primary AML blasts and stem/progenitor cells resistant to or relapsed after venetoclax-based therapy irrespective of mutations and cytogenetic abnormalities. Venetoclax and AMG176 combination markedly suppressed antiapoptotic BCL-2 proteins and AML stem/progenitor cells and dramatically extended mouse survival (median 336 vs. control 126 days; P < 0.0001) in a patient-derived xenograft (PDX) model developed from a venetoclax/hypomethylating agent therapy-resistant patient with AML. However, decreased BAX levels in the bone marrow residual leukemia cells after 4-week combination treatment may represent a resistance mechanism that contributed to their survival. Enhanced antileukemia activity was also observed in a PDX model of monocytic AML, known to be resistant to venetoclax therapy. Our results support codependence on multiple antiapoptotic BCL-2 proteins and suppression of BAX as mechanisms of AML resistance to individual BH3 mimetics. Cotargeting of MCL-1 and BCL-2 eliminates otherwise apoptosis-resistant cells.
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