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.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.3 R&D Unit, Institut de Recherches Servier Oncology, Croissy Sur Seine, FranceAcute myeloid leukemia (AML) is a hematopoietic malignancy arising from the transformation of myeloid progenitor cells
We have recently shown that combined targeting of BCL-2 with venetoclax and direct inhibition of MCL1 with a lentiviral BH3-expressing vector was highly effective in producing prolonged remissions in xenograft models of acute myeloid leukemia (AML) [14]
We first compared the pro-survival dependency of primary AML samples treated with a panel of potent and selective inhibitors of MCL1 (S63845), BCL-2 (ABT-199/venetoclax or S55746/BCL201), or BCL-XL (A1331852)
Summary
Treatment options have remained static for decades, the FDA has recently approved four AML therapies in 2017, including midostaurin, CPX-351, gemtuzumab ozogomycin, and enasidenib [3]. Another promising strategy involves targeting pro-survival activity in AML with BH3-mimetics designed to target BCL-2 and related family members [4]. Other BH3-mimetics selectively targeting other pro-survival proteins include A1331852, which inhibits BCL-XL and the recently described MCL1 inhibitor S63845, which our group has shown to be well tolerated in mice and active against a number of malignancies, including a subset of AML at low nanomolar concentrations [8, 9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
