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Cotargeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells
- Source :
- Cancer Research. 78:3075-3086
- Publication Year :
- 2018
- Publisher :
- American Association for Cancer Research (AACR), 2018.
-
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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 78
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....900faa775cd20cb08d5d52bcd366b2c3