Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics

Abstract

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53–wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic–driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation.

A Novel Approach for Glioblastoma Treatment by Combining Apoptosis Inducers (TMZ, MTX, and Cytarabine) with E.V.A. (Eltanexor, Venetoclax, and A1210477) Inhibiting XPO1, Bcl-2, and Mcl-1

“…As was shown before, treatment with Eltanexor induces XPO1 gene expression in U87 and U251 cells, likely as a compensatory response [34]. Given that Mcl-1 confers resistance to BH3-mimetics targeting Bcl-2 [41], we examined Bcl-2, Mcl-1, and XPO1 expression changes following treatment with BH3-mimetics (A1210477, Venetoclax) and Eltanexor, individually or in combination, in both GB cell lines and GSCs. qPCR was performed to detect Bcl-2, Mcl-1, and XPO1 mRNA expression post-treatment with the individual inhibitors alone (Figure 4A-C) or combined (Figure 4D-F).…”

“…Interestingly, Bcl-2 inhibition triggers Mcl-1 upregulation in GB cells in order to compensate for the tasks Bcl-2 would usually undertake to save the cell from apoptosis [39]. Currently, the combination of Bcl-2-and Mcl-1-inhibitors (e.g., A1210477) is being proposed and discussed for treatment of various cancers in preclinical and clinical trials, including GB [40][41][42]. Furthermore, synergistical links between p53 and Mcl-1 have already been described [43].…”

Venetoclax Resistance in Acute Myeloid Leukemia

“…There is a strong rationale for targeting MCL1 anti-apoptotic protein in preclinical models based on dependency of AML cells for sustaining blast proliferation [ 42 , 75 , 79 , 128 , 129 ]. Nevertheless, clinical development was halted by cardiac toxicity (mainly troponin elevations).…”