MERTK抑制剂MRX-2843在临床前模型中使AML对venetoclax和azacitidine增敏

While many patients with acute myeloid leukemia (AML) have an initial favorable response to treatment with standard of care venetoclax, a BCL2 inhibitor, and azacitidine, a DNA methyltransferase inhibitor, sustained remissions remain elusive and new therapies are urgently needed. We identified MERTK (MER Receptor Tyrosine Kinase) as a potential therapeutic target in AML and developed MRX-2843, a first-in-class dual MERTK/FLT3 kinase inhibitor that is currently being tested in leukemia patients. Here we describe a novel therapy that combines MRX-2843 with venetoclax and azacitidine to provide enhanced therapeutic effects in preclinical AML models. In human AML cell line cultures (KG-1, OCI-AML5, and NOMO-1), treatment with the 3-drug combination (MRX-2843/venetoclax/azacitidine) reduced cell density compared to venetoclax/azacitidine. Mathematical modeling using the fractional product method revealed a synergistic interaction between MRX-2843 and venetoclax/azacitidine in 2 of the 3 cell lines and an additive interaction in the other. In all 3 cell lines, MRX-2843 synergized with venetoclax/azacitidine to increase induction of cell death compared to venetoclax/azacitidine alone. Furthermore, in all 3 cell lines, the 3-drug combination reduced levels of c-MYC protein compared to venetoclax/azacitidine. These findings reveal a potential mechanism of the enhanced therapeutic effects mediated by the 3-drug combination. The triple combination also provided enhanced therapeutic effects against the KG1 cell line in an AML organoid model system that mimics many features of the bone marrow microenvironment, including chemoprotection. These data support addition of MRX-2843 to current standard of care venetoclax/azacitidine to better target bone marrow disease. Indeed, the 3-drug regimen significantly reduced bone marrow disease burden and prolonged survival in immune-compromised mice inoculated with the KG1 AML cell line. After the first treatment cycle (28 days), the fraction of human CD45+ leukemia cells in the bone marrow was significantly reduced in mice treated with the 3-drug combination (8.5±5%, n=4) compared to vehicle (67±8%, n=5, p<0.001), MRX-2843 (41±9%, n=6, p=0.0451), or venetoclax/azacitidine (40%±8%, n=6, p=0.0482). Moreover, mouse survival was significantly prolonged by the triple combination (median survival > 150 days, 59.1% survival after 150 days of treatment) compared to MRX-2843 (median survival = 76.5 days, 0% survival at 150 days, p<0.0001) or venetoclax/azacitidine (median survival = 104.5 days, 4.6% survival at 150 days, p<0.001). Together these findings (i) implicate co-administration of MRX-2843, venetoclax and azacitidine as an effective strategy to treat AML, (ii) reveal a potential mechanistic basis for this strategy, and (iii) support evaluation of this novel 3-drug combination in future clinical trials.