1. Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia
- Author
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Lan Zhang, Y. Wang, Jessica M. Salmon, Corina Ghiurau, Andrew H. Wei, David C.S. Huang, Donia M Moujalled, Audrey Claperon, Olivier Geneste, Sarah MacRaild, Ping Lan, Guillaume Lessene, David J. Segal, Ana Leticia Maragno, Frédéric Colland, Tse-Chieh Teh, Laurence Kraus-Berthier, Adrien Zichi, Francesca Rocchetti, Giovanna Pomilio, Andrew W. Roberts, Adam Ivey, Ing Soo Tiong, Erick Morris, Maïa Chanrion, Ensar Halilovic, and Sewa Rijal
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Myeloid ,Mice, SCID ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Biomimetics ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,MCL1 ,Sulfonamides ,Hematology ,Myeloid leukemia ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,030220 oncology & carcinogenesis ,Drug Therapy, Combination ,Female ,medicine.medical_specialty ,Antineoplastic Agents ,Thiophenes ,Article ,Acute myeloid leukaemia ,03 medical and health sciences ,Proto-Oncogene Proteins ,Internal medicine ,medicine ,Animals ,Humans ,Venetoclax ,business.industry ,Translational research ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Xenograft Model Antitumor Assays ,Peptide Fragments ,Myeloid Cell Leukemia Sequence 1 Protein ,Pyrimidines ,030104 developmental biology ,chemistry ,Cancer research ,Bone marrow ,business - 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.
- Published
- 2018
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