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 ineffectiveness of MCL-1 inhibitor AMG176 in venetoclax-resistant, and conversely, of venetoclax in AMG176-resistant 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. Co-targeting 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 anti-apoptotic BCL-2 proteins and AML stem/progenitor cells and dramatically extended mouse survival (median 336 vs control 126 d, P<0.0001) in a PDX model developed from a venetoclax/hypomethylating agent therapy-resistant AML patient. However, decreased BAX levels in the bone marrow residual leukemia cells after 4-wk combination treatment may represent a resistance mechanism that contributed to their survival. Enhanced anti-leukemia activity was also observed in a PDX model of monocytic AML, known to be resistant to venetoclax therapy. Our results support co-dependence on multiple anti-apoptotic BCL-2 proteins and suppression of BAX as mechanisms of AML resistance to individual BH3 mimetics. Co-targeting of MCL-1 and BCL-2 eliminates otherwise apoptosis-resistant cells.

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