Faculty, Staff and Student Publications
Publication Date
6-1-2022
Journal
Molecular Cancer Therapeutics
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.
Keywords
Animals, Apoptosis, Apoptosis Regulatory Proteins, Biomimetic Materials, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Humans, Leukemia, Myeloid, Acute, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Proto-Oncogene Proteins c-bcl-2, Stem Cells, bcl-2-Associated X Protein, MCL-1, BCL-2, apoptosis, AML stem cells
DOI
10.1158/1535-7163.MCT-21-0690
PMID
35364607
PMCID
PMC9167707
PubMedCentral® Posted Date
12-1-2022
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
no
Included in
Bioinformatics Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Biomedical Informatics Commons, Oncology Commons