Corina Ghiurau

AVL (France)

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Audrey Clapéron

Servier (France)

Frédéric Colland

Institut des Hautes Études Scientifiques

Lan Zhang

Kunming Medical University

Francesca Rocchetti

Servier (France)

Erick J. Morris

Renaissance Computing Institute

Olivier Geneste

Servier (France)

Laurence Kraus‐Berthier

Servier (France)

Donia Moujalled

University of Melbourne

Jessica M. Salmon

Peter MacCallum Cancer Centre

Andrew W. Roberts

Walter and Eliza Hall Institute of Medical Research

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Walter and Eliza Hall Institute of Medical Research

Monash University

Australian Centre for HIV and Hepatitis Virology Research

Servier (France)

AVL (France)

University of Melbourne

The Alfred Hospital

Institut des Hautes Études Scientifiques

Centre National de la Recherche Scientifique

Alfred Health

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

Leukemia (2018)

Donia Moujalled Giovanna Pomilio Corina Ghiurau Adam Ivey Jessica M. Salmon

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.

MCL1

Venetoclax

Azacitidine

10.1038/s41375-018-0261-3

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