Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/119858
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Type: Journal article
Title: Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia
Author: Moujalled, D.
Pomilio, G.
Ghiurau, C.
Ivey, A.
Salmon, J.
Rijal, S.
Macraild, S.
Zhang, L.
Teh, T.
Tiong, I.
Lan, P.
Chanrion, M.
Claperon, A.
Rocchetti, F.
Zichi, A.
Kraus-Berthier, L.
Wang, Y.
Halilovic, E.
Morris, E.
Colland, F.
et al.
Citation: Leukemia, 2019; 33(4):905-917
Publisher: Springer Nature
Issue Date: 2019
ISSN: 0887-6924
1476-5551
Statement of
Responsibility: 
Donia M. Moujalled, Giovanna Pomilio, Corina Ghiurau, Adam Ivey, Jessica Salmon, Sewa Rijal, Sarah Macraild, Lan Zhang, Tse-Chieh Teh, Ing-Soo Tiong, Ping Lan, Maia Chanrion, Audrey Claperon, Francesca Rocchetti, Adrien Zichi, Laurence Kraus-Berthier, Youzhen Wang, Ensar Halilovic, Erick Morris, Frédéric Colland, David Segal, David Huang, Andrew W. Roberts, Ana Leticia Maragno, Guillaume Lessene, Olivier Geneste, Andrew H. Wei
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.
Keywords: Tumor Cells, Cultured; Animals; Mice, Inbred NOD; Humans; Mice; Mice, SCID; Sulfonamides; Pyrimidines; Thiophenes; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Antineoplastic Agents; Drug Therapy, Combination; Xenograft Model Antitumor Assays; Biomimetics; Female; Male; Leukemia, Myeloid, Acute; Myeloid Cell Leukemia Sequence 1 Protein; Bridged Bicyclo Compounds, Heterocyclic
Rights: © The Author(s) 2018. This article is published with open access Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
RMID: 0030098582
DOI: 10.1038/s41375-018-0261-3
Appears in Collections:Medicine publications

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