Therapeutic Targeting of MERTK and BCL-2 in T-Cell and Early T-Precursor Acute Lymphoblastic Leukemia

SIMPLE SUMMARY: Children with T-cell leukemia (T-ALL) who experience relapse have a low chance of a cure with current therapy; so, new medicines are needed. MERTK and BCL-2 are proteins that may be therapeutic targets in children with T-ALL. In this research we tested whether treatments targeting MERTK and BCL-2 are effective in experimental models of T-ALL. We found that MERTK and BCL-2 are present in some T-ALL cells and showed that a new drug called MRX-2843, which blocks MERTK function, can kill T-ALL cells. In mice with T-ALL, treatment with MRX-2843 reduced the presence of leukemia cells and prolonged survival. We also found that MRX-2843 provided more effective T-ALL cell killing when it was combined with another drug called venetoclax, which blocks BCL-2 function. These studies provide good evidence that MRX-2843 could be effective for treatment of T-ALL, especially when combined with venetoclax. ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of childhood ALL. The early T-precursor (ETP-ALL) subset is characterized by an immature T-cell phenotype, chemoresistance, and high rates of induction failure. MERTK receptor tyrosine kinase is ectopically expressed in half of T-ALLs, particularly those with an immature T-cell phenotype, suggesting a role in ETP-ALL. The anti-apoptotic protein B-cell lymphoma-2 (BCL-2) is essential for ETP-ALL cell survival. Here, we show that MERTK and BCL-2 mRNA and protein are preferentially expressed in ETP-ALL patient samples. The dual MERTK/FLT3 inhibitor MRX-2843 decreased MERTK activation and downstream signaling, inhibited cell expansion, and induced cell death in ETP-ALL cell lines. Further, 54% (21/39) of primary T-ALL patient samples were sensitive to MERTK inhibition. Treatment with MRX-2843 significantly reduced leukemia burden and prolonged survival in cell-line-derived T-ALL and ETP-ALL xenograft models. In a patient-derived ETP-ALL xenograft model, treatment with MRX-2843 markedly reduced peripheral blood leukemia and spleen weight compared to vehicle-treated mice and prolonged survival. MRX-2843 also synergized with venetoclax to provide enhanced anti-leukemia activity in ETP-ALL cell cultures, with a dose ratio of 1:20 MRX-2843:venetoclax providing optimal synergy. These data demonstrate the therapeutic potential of MRX-2843 in patients with T-ALL and provide rationale for clinical development. MRX-2843 monotherapy is currently being tested in patients with relapsed leukemia (NCT04872478). Further, our data indicate that combined MERTK and BCL-2 inhibition may be particularly effective for treatment of ETP-ALL.