The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia

Abstract

FMS-like tyrosine kinase 3–targeted (FLT3-targeted) therapies have shown initial promise for the treatment of acute myeloid leukemia (AML) expressing FLT3-activating mutations; however, resistance emerges rapidly. Furthermore, limited options exist for the treatment of FLT3-independent AML, demonstrating the need for novel therapies that reduce toxicity and improve survival. MERTK receptor tyrosine kinase is overexpressed in 80% to 90% of AMLs and contributes to leukemogenesis. Here, we describe MRX-2843, a type 1 small-molecule tyrosine kinase inhibitor that abrogates activation of both MERTK and FLT3 and their downstream effectors. MRX-2843 treatment induces apoptosis and inhibits colony formation in AML cell lines and primary patient samples expressing MERTK and/or FLT3-ITD, with a wide therapeutic window compared with that of normal human cord blood cells. In murine orthotopic xenograft models, once-daily oral therapy prolonged survival 2- to 3-fold over that of vehicle-treated controls. Additionally, MRX-2843 retained activity against quizartinib-resistant FLT3-ITD–mutant proteins with clinically relevant alterations at the D835 or F691 loci and prolonged survival in xenograft models of quizartinib-resistant AML. Together, these observations validate MRX-2843 as a translational agent and support its clinical development for the treatment of AML.

Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia

“…Resistance has been reported to occur through multiple mechanisms such as transformation of the drug target through genetic variation (indels or single base modifications), overexpression, and alternative signal transduction (28). Knowledge of the mechanisms of drug-induced resistance can lead to insights for combinations and rational small molecule drug design to develop compounds for overcoming drug resistance (29)(30)(31). Point mutations within the coding region of the target are a frequent cause for resistance to targeted therapies and have been observed clinically in acute myeloid leukemia (AML) with small molecules such as FMS-like tyrosine kinase-3 (FLT3) inhibitors (32,33).…”

Targeting the TAM Receptors in Leukemia

“…Conversely, shRNA knockdown of MERTK increased expression of genes encoding pro-apoptotic proteins BAX , PMAIP1 (NOXA), and BBC3 (PUMA) [24]. These changes in downstream apoptotic signaling promote tumor cell survival and inhibition of MERTK using shRNA or small molecule inhibitors induced apoptosis and inhibited colony formation in AML and ALL cell lines and AML patient samples [24,53,54]. In orthotopic cell line and patient-derived xenograft models, MERTK inhibition decreased tumor burden and prolonged survival, implicating MERTK as a therapeutic target [24,49,54].…”

“…These changes in downstream apoptotic signaling promote tumor cell survival and inhibition of MERTK using shRNA or small molecule inhibitors induced apoptosis and inhibited colony formation in AML and ALL cell lines and AML patient samples [24,53,54]. In orthotopic cell line and patient-derived xenograft models, MERTK inhibition decreased tumor burden and prolonged survival, implicating MERTK as a therapeutic target [24,49,54]. Additionally, inhibition of MERTK enhanced sensitivity to standard cytotoxic chemotherapies in B-ALL and T-ALL cell lines [24,49], suggesting that clinical application of MERTK inhibitors could be most therapeutically effective in combination with other agents, rather than as a monotherapy.…”

“…In addition, UNC2025 mediated potent anti-leukemia activity in approximately one third of 261 primary leukemia patient samples and the AML and T-ALL subsets were particularly sensitive, with 40% to 50% of samples responding to treatment with UNC2025, suggesting that a large portion of patients with leukemia could benefit from treatment with UNC2025 or similar compounds and supporting continued clinical development. Toward this end, MRX-2843, an analog to UNC2025 with a minor side chain substitution and similar PK properties and toxicity profile [54,109], was recently approved by the Food and Drug Administration (FDA) for clinical testing. Like UNC2025, MRX-2843 induced apoptosis, and inhibited colony formation in MERTK-expressing leukemia cell cultures.…”

“…Additionally, MRX-2843 prolonged survival 2–3 fold compared to vehicle controls in both cell line and patient derived xenograft (PDX) models of AML. Importantly, these compounds are 10–20 fold more potent against leukemia cells compared to normal human cord blood mononuclear cells in colony formation assays, indicating potential for a wide therapeutic window [54,110]. …”