| Abstract: |
PURPOSE: Acute myelogenous leukemia (AML) is an aggressive disease with a poor outcome. We investigated mechanisms by which the anti-AML activity of ABT-199 (venetoclax) could be potentiated by dual mTORC1/TORC2 inhibition. EXPERIMENTAL DESIGN: Venetoclax/INK128 synergism was assessed in various AML cell lines and primary patient AML samples in vitro. AML cells overexpressing MCL-1, constitutively active AKT, BAK, and/or BAX knockout, and acquired venetoclax resistance were investigated to define mechanisms underlying interactions. The antileukemic efficacy of this regimen was also examined in xenograft and patient-derived xenograft (PDX) models. RESULTS: Combination treatment with venetoclax and INK128 (but not the mTORC1 inhibitor rapamycin) dramatically enhanced cell death in AML cell lines. Synergism was associated with p-AKT and p-4EBP1 downregulation and dependent upon MCL-1 downregulation and BAK/BAX upregulation as MCL-1 overexpression and BAX/BAK knockout abrogated cell death. Constitutive AKT activation opposed synergism between venetoclax and PI3K or AKT inhibitors, but not INK128. Combination treatment also synergistically induced cell death in venetoclax-resistant AML cells. Similar events occurred in primary patient-derived leukemia samples but not normal CD34+ cells. Finally, venetoclax and INK128 co-treatment displayed increased antileukemia effects in in vivo xenograft and PDX models. CONCLUSIONS: The venetoclax/INK128 regimen exerts significant antileukemic activity in various preclinical models through mechanisms involving MCL-1 downregulation and BAK/BAX activation, and offers potential advantages over PI3K or AKT inhibitors in cells with constitutive AKT activation. This regimen is active against primary and venetoclax-resistant AML cells, and in in vivo AML models. Further investigation of this strategy appears warranted. ©2023 American Association for Cancer Research. |
| Keywords: |
protein kinase b; genetics; leukemia, myeloid, acute; metabolism; cell death; protein bcl 2; apoptosis; cell line, tumor; phosphatidylinositol 3 kinase; protein mcl 1; tumor cell line; proto-oncogene proteins c-akt; fused heterocyclic rings; proto-oncogene proteins c-bcl-2; protein bax; mammalian target of rapamycin complex 1; bcl-2-associated x protein; phosphatidylinositol 3-kinases; acute myeloid leukemia; myeloid cell leukemia sequence 1 protein; humans; human; venetoclax; bcl2 protein, human; bridged bicyclo compounds, heterocyclic; mechanistic target of rapamycin complex 1
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