Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells
Autor: | Mohamed Rahmani, Andrea Ferreira-Gonzalez, Rebecca E. Parker, Steven Grant, Xin-Yan Pei, Maciej Kmieciak, Jewel Nkwocha, Deepak Sampath, Elisa Hawkins, Joel D. Leverson |
---|---|
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cancer Research Myeloid CD34 Down-Regulation Apoptosis Mice SCID Article Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Mice Inbred NOD Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans neoplasms Protein kinase B PI3K/AKT/mTOR pathway bcl-2-Associated X Protein Sulfonamides Venetoclax Myeloid leukemia U937 Cells Bridged Bicyclo Compounds Heterocyclic medicine.disease Mitochondria Leukemia Myeloid Acute Leukemia Pyrimidines 030104 developmental biology medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Oncology chemistry 030220 oncology & carcinogenesis Cancer research Heterografts Apoptosis Regulatory Proteins |
Zdroj: | Cancer Research. 78:3075-3086 |
ISSN: | 1538-7445 0008-5472 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |