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

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.

BH3-Mimetic Drugs: Blazing the Trail for New Cancer Medicines

“…These malignant cells could be killed by a combination of venetoclax plus BH3-mimetics targeting either BCL-XL or MCL-1, showing that the ability of targeting BCL-2 had remained intact (Tahir et al, 2017). Combining two or even more BH3-mimetic drugs to inhibit several pro-survival BCL-2 proteins, either simultaneously or sequentially, may be an attractive approach to cancer therapy Khaw et al, 2016;Moujalled et al, 2018;Ramsey et al, 2018;Teh et al, 2018). However, it will be important to ensure that such strategies will not cause unacceptable on-target side effects, since combination targeting of MCL-1 and BCL-XL was reported to be lethal in mouse models, due to acute liver toxicity (Weeden et al, 2018).…”

“…Clinical studies showed that the combination of venetoclax with HMA or LDC has reduced efficacy in patients with chemotherapy-relapsed or refractory AML (Aldoss et al, 2018;DiNardo et al, 2018b). An intriguing approach to enhance the activity of venetoclax in such resistant AML cases may involve directly targeting both BCL-2 and MCL-1, a strategy shown to be effective in pre-clinical AML model systems in vivo Moujalled et al, 2018;Ramsey et al, 2018;Teh et al, 2018). The emergence of potent MCL-1 inhibitors has made this feasible, and phase 1 clinical studies verifying the safety of S63845 and AMG 176 in humans are currently underway.…”

MCL1 inhibition is effective against a subset of small-cell lung cancer with high MCL1 and low BCL-XL expression

“…There are several studies on double inhibition of MCL1 and BCL-2. The combination of S63845 with venetoclax, which is a FDA-approved BCL-2 inhibitor, has potent activity against nasopharyngeal carcinoma, acute myeloid leukemia, and mantle cell lymphoma without severe toxicity 26,41,42 . Consistent with this, venetoclax and S63845 may have synergistic efficacy against SCLC.…”

MCL1 dependence across MDS subtypes and dual inhibition of MCL1 and BCL2 in MISTRG6 mice

“…CBL and PTPN11 in this cohort) [14][15][16][17][18] . 38 and in vivo 11 is limited at clinically meaningful doses.…”