MRX-2843, a dual MERTK and FLT3 inhibitor, mediates synergistic anti-leukemia activity in combination with BCL-2 inhibitors in acute myeloid leukemia and early T-cell precursor acute lymphoblastic leukemia

Abstract While overall outcomes have improved for patients with acute leukemia, high-risk subsets including acute myeloid leukemia (AML) and relapsed/refractory early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) continue to have poor prognosis. New therapies are urgently needed. Both MERTK tyrosine kinase and the anti-apoptotic protein BCL-2 have been implicated as therapeutic targets in AML and ETP-ALL. We developed MRX-2843, a novel small molecule MERTK and FLT3 inhibitor currently in clinical trials in patients with leukemia. The BCL-2 inhibitor venetoclax is FDA-approved for treatment of AML and has clinical activity in relapsed/refractory T-ALL. Here, we investigated the impact of treatment with MRX-2843 in combination with BCL-2 inhibitors in preclinical models. Human AML and ETP-ALL cell lines were treated with MRX-2843 and/or a BCL-2 inhibitor for 48-72 hours and relative cell numbers were determined using CellTiter-Glo reagent. Synergy was assessed by mathematical modeling using the response additivity and fractional product methods. Combined treatment with MRX-2843 and venetoclax provided enhanced therapeutic efficacy compared to MRX-2843 or venetoclax alone. The interaction between drugs was dose-dependent and synergistic in AML cell lines. For instance, in KG-1 cells combined treatment with an IC50 concentration of MRX-2843 and an IC15 concentration of venetoclax reduced cell density by 88 ± 4.0% and the combination was significantly more effective than MRX-2843 or venetoclax alone (p < 0.0001, 2-way ANOVA). Moreover, the 88% reduction in cell density in cultures treated with the combination was significantly greater than the 58 ± 1.6% reduction expected for an additive interaction (p < 0.0001). Robust therapeutic activity and dramatic synergy were also observed in NOMO-1 and OCI-AML5 cell cultures treated with the combination and the interaction between drugs was additive or synergistic in Loucy ETP-ALL cells. Enhanced therapeutic efficacy and synergistic interactions were also observed in AML cell cultures treated with MRX-2843 and navitoclax, a BCL-2 and BCL-XL inhibitor, implicating BCL-2 inhibition as a mechanism of synergy. In a high-throughput screen, MRX-2843 mediated synergistic anti-leukemia activity in combination with venetoclax in all 7 AML and both ETP-ALL cell lines tested. Synergy was optimal when MRX-2843 and venetoclax were administered in a 1:20 ratio. Our data (i) implicate combined treatment with MRX-2843 and a BCL-2 inhibitor, such as venetoclax, as a promising new strategy for treatment of both AML and ETP-ALL, (ii) define optimized dosing strategies for MRX-2843 and venetoclax combination therapy, and (iii) support further evaluation of MRX-2843 in combination with venetoclax in murine models and potentially in upcoming clinical trials. Citation Format: Aashis Thapa, Juhi Jain, Ryan J. Summers, James M. Kelvin, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Erik C. Dreaden, Deborah DeRyckere, Douglas K. Graham. MRX-2843, a dual MERTK and FLT3 inhibitor, mediates synergistic anti-leukemia activity in combination with BCL-2 inhibitors in acute myeloid leukemia and early T-cell precursor acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3339.