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Leukemia. 2018 Feb;32(2):303-312. doi: 10.1038/leu.2017.243. Epub 2017 Jul 28.

Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1.

Author information

1
Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
2
Department of Clinical Haematology, The Alfred Hospital, Melbourne, Victoria, Australia.
3
Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia.
4
Departments of Medicine and Medical Biology, Faculty of Medicine, University of Melbourne, Parkville, Victoria. Australia.
5
Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
6
Peter MacCallum Cancer Centre, Parkville, Victoria, Australia.
7
Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
8
Department of Clinical Hematology and BMT, The Royal Melbourne Hospital, Royal Parade, Parkville, Victoria, Australia.

Abstract

Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on pro-apoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.

PMID:
28751770
DOI:
10.1038/leu.2017.243

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