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Leukemia. 2019 Apr;33(4):905-917. doi: 10.1038/s41375-018-0261-3. Epub 2018 Sep 10.

Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia.

Author information

1
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
2
Department of Clinical Haematology, The Alfred Hospital, Melbourne, Australia.
3
R&D Unit, Institut de Recherches Servier Oncology, Croissy Sur Seine, France.
4
Oncology Disease Area, Novartis Institutes for BioMedical Research, 4056, Basel, Switzerland.
5
Department of Pathology, The Alfred Hospital, Melbourne, Australia.
6
The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
7
Oncology Disease Area, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
8
Department of Medical Biology, The University of Melbourne, Parkville, Australia.
9
Department of Clinical Haematology, Royal Melbourne Hospital, Melbourne, Australia.
10
Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Australia.
11
Australian Centre for Blood Diseases, Monash University, Melbourne, Australia. a.wei@alfred.org.au.
12
Department of Clinical Haematology, The Alfred Hospital, Melbourne, Australia. a.wei@alfred.org.au.
13
Department of Pathology, The Alfred Hospital, Melbourne, Australia. a.wei@alfred.org.au.

Abstract

Improving outcomes in acute myeloid leukemia (AML) remains a major clinical challenge. Overexpression of pro-survival BCL-2 family members rendering transformed cells resistant to cytotoxic drugs is a common theme in cancer. Targeting BCL-2 with the BH3-mimetic venetoclax is active in AML when combined with low-dose chemotherapy or hypomethylating agents. We now report the pre-clinical anti-leukemic efficacy of a novel BCL-2 inhibitor S55746, which demonstrates synergistic pro-apoptotic activity in combination with the MCL1 inhibitor S63845. Activity of the combination was caspase and BAX/BAK dependent, superior to combination with standard cytotoxic AML drugs and active against a broad spectrum of poor risk genotypes, including primary samples from patients with chemoresistant AML. Co-targeting BCL-2 and MCL1 was more effective against leukemic, compared to normal hematopoietic progenitors, suggesting a therapeutic window of activity. Finally, S55746 combined with S63845 prolonged survival in xenograft models of AML and suppressed patient-derived leukemia but not normal hematopoietic cells in bone marrow of engrafted mice. In conclusion, a dual BH3-mimetic approach is feasible, highly synergistic, and active in diverse models of human AML. This approach has strong clinical potential to rapidly suppress leukemia, with reduced toxicity to normal hematopoietic precursors compared to chemotherapy.

PMID:
30214012
DOI:
10.1038/s41375-018-0261-3

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