AMG 176 exhibits robust antitumor activity in combination with standard of care agents in models of acute myeloid leukemia

Acute myeloid leukemia (AML) is a heterogeneous malignancy involving the clonal expansion of abnormal myeloid progenitor cells. The anti-apoptotic BCL-2 protein family member MCL1 has been implicated in AML pathogenesis. AMG 176 is a potent and selective MCL1 inhibitor currently being evaluated in an AML Phase I clinical trial. Standard of care (SOC) treatment for AML involves “7+3” induction therapy with cytarabine and an anthracycline (i.e. doxorubicin). In patient’s ineligible for conventional induction therapy, the hypomethylating agent decitabine is a well-tolerated alternative. Here we investigate the activity of AMG 176 and AM-8621, a closely related analog of AMG 176 with similar potency and selectivity, in combination with SOC therapies in preclinical models of AML. We profiled a panel of AML cell lines (MOLM-13, MV-4-11, GDM-1 and EOL-1), testing AM-8621 in combination with cytarabine, doxorubicin and decitabine in 3-day viability assays. Evidence for synergistic activity was detected with each of the combinations across subsets of the cell lines. A time course of AM-8621 treatment revealed a rapid induction of caspase 3/7 activity, with significant increases observed within the first 2-4 hours of treatment while longer duration treatment (>8 hours) was required to activate caspase 3/7 with SOC agents. Combined treatment with AM-8621 and SOC agents exhibited significant improvements in caspase 3/7 activity beyond either single agent alone. To provide mechanistic insight into the ability of SOC agents to sensitize AML cell lines to AM-8621 treatment, signaling experiments were performed to characterize changes in BCL-2 protein family members following treatment with SOC agents. Clear changes in the levels of anti-apoptotic BCL-2 family members (MCL1, BCL-2 and BCL-XL), BH3-only domain containing proteins (BIM, NOXA, PUMA) and the executioner protein BAK were observed, providing insight into potential mechanisms of priming cells to MCL1 inhibition. Combinations of AMG 176 and each of the SOC therapies were also tested in a MOLM-13 orthotopic xenograft model of AML. Mice were treated with combinations of AMG 176 and cytarabine, decitabine or doxorubicin and compared against the single agent therapies. Significant reductions in tumor burden compared to single agent treatments were observed with the AMG 176 + doxorubicin (30% regression) and AMG 176 + decitabine (98% tumor growth inhibition) combinations. These data highlight the promise of combining AMG 176 with SOC therapies in the setting of AML. Citation Format: Sean Caenepeel, Brian Belmontes, Tao Osgood, Elaina Cajulis, Angela Coxon, Jude Canon, Paul E. Hughes. AMG 176 exhibits robust antitumor activity in combination with standard of care agents in models of acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2180.