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Targeting AML MCL-1 re-sensitizes BCL-2 inhibition
Discussion
Here, we demonstrate that co-targeting BCL-2 and MCL-1 is highly effective in AML cell lines and primary patient samples, which is consistent with recent reports.23,24,26,29 Importantly, combined MCL-1 and BCL-2 inhibition was highly synergistic against AML stem/prog- enitor cells and exerted pronounced anti-leukemia activity in venetoclax-resistant AML patient samples in vitro, even under conditions mimicking the BM stromal microenvi- ronment. Furthermore, similar findings were obtained in a unique PDX model of clinical venetoclax/decitabine- relapsed AML. Hence, the combination is not just more effective than each agent given alone, but has the potential to overcome intrinsic and acquired venetoclax resistance. In exploring the mechanisms underlying the combina- tion’s efficacy, we demonstrated that targeting MCL-1 sensitizes to BCL-2 inhibition in AML through not only
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cooperative release of pro-apoptotic from binding to anti- apoptotic BCL-2 proteins but also inhibition of cell metab- olism and key stromal microenvironmental mechanisms. The metabolic and stromal functions of MCL-1 can appar- ently act independently of the protein’s anti-apoptotic activity. These findings provide rationale for the clinical development of combined BCL-2 and MCL-1 targeting in resistant/relapsed AML patients, particularly in patients who were resistant/relapsed from venetoclax-based thera- pies.
We observed that WT1- or BCORL1-mutated primary AML samples were particularly resistant to AZD5991 and AZD4573, respectively. WT1 mutation in AML is associat- ed with poor outcomes and chemoresistance,44 and BCORL1 encodes a transcription co-repressor, opposite to CDK9. We speculate that BCORL1-mutated cells are less transcriptionally suppressed, and therefore more resistant to CDK9 inhibition. However, the sample size for either
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Figure 6. Continued on following page.
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