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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

Moujalled, Donia and Pomilio, Giovanna and Ghiurau, Corina and Ivey, Adam and Salmon, Jessica and Rijal, Sewa and Macraild, Sarah and Zhang, Lan and Teh, Tse-Chieh and Tiong, Ing-Soo and Lan, Ping and Schaeffer, Fabienne and Von Arx, Fabian and Chanrion, Maia and Claperon, Audrey and Rocchetti, Francesca and Kraus-Berthier, Laurence and Wang, Youzhen and Halilovic, Ensar and Morris, Erick and Colland, Frederic and Segal, David and Mistry, Prakash and Huang, David and Roberts, Andrew and Maragno, Ana Leticia and Lessene, Guillaume and Geneste, Olivier and Wei, Andrew (2018) Combining BH3-Mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. Leukemia. ISSN 14765551

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.

Item Type: Article
Date Deposited: 14 Nov 2018 00:45
Last Modified: 14 Nov 2018 00:45
URI: https://oak.novartis.com/id/eprint/36362

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