Supplementary Figures S1: Activity of combined treatment with venetoclax and GDC-0980 in human AML cells. Supplementary Figures S1: Synergistic interaction between venetoclax and GDC-0980 using median dose effect analysis. Supplementary Figures S3: Effects of venetoclax/GDC-0980 on PI3K/AKT/mTOR pathway activity and BCL-2 members expression. Supplementary Figure S4: Mutation analysis of primary AML specimens using targeted next-generation sequencing. Supplementary Figure S5. Combined treatment with venetoclax/GDC-0980 or taselisib exhibits potent in vivo anti-AML activity without significant toxicity Supplementary Figure S6. BIM is not required for BAX activation by venetoclax or venetoclax/GDC-0980, and Mcl-1 downregulation plays a significant functional role in venetoclax/GDC-0980 lethality. Supplementary Figure S7. Mitochondrial BAX translocation in venetoclax-resistant MV4-11 cells following combined treatment
ARTICLE ABSTRACT
Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients, suggesting that targeting BCL-2 alone is insufficient to yield durable responses. Here, we assessed the efficacy of coadministration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition. Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen. Combined treatment was also effective against primary AML blasts from 17 patients, including those bearing various genetic abnormalities. Venetoclax/GDC-0980 markedly induced apoptosis in primitive CD34+/38−/123+ AML cell populations but not in normal hematopoietic progenitor CD34+ cells. The regimen was also active against AML cells displaying intrinsic or acquired venetoclax resistance or tumor microenvironment–associated resistance. Either combinatorial treatment markedly reduced AML growth and prolonged survival in a systemic AML xenograft mouse model and diminished AML growth in two patient-derived xenograft models. Venetoclax/GDC-0980 activity was partially diminished in BAK−/− cells and failed to induce apoptosis in BAX−/− and BAX−/−BAK−/− cells, whereas BIM−/− cells were fully sensitive. Similar results were observed with venetoclax alone in in vitro and in vivo systemic xenograft models. Collectively, these studies demonstrate that venetoclax/GDC-0980 exhibits potent anti-AML activity primarily through BAX and, to a lesser extent, BAK. These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.Significance: Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia. Cancer Res; 78(11); 3075–86. ©2018 AACR.
