The MERTK/FLT3 inhibitor MRX-2843 overcomes resistance-conferring FLT3 mutations in acute myeloid leukemia
Katherine A. Minson, Catherine C. Smith, Deborah DeRyckere, Clara Libbrecht, Alisa B. Lee-Sherick, Madeline G. Huey, Elisabeth A. Lasater, Gregory D. Kirkpatrick, Michael A. Stashko, Weihe Zhang, Craig T. Jordan, Dmitri Kireev, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Neil P. Shah, Douglas K. Graham
Katherine A. Minson, Catherine C. Smith, Deborah DeRyckere, Clara Libbrecht, Alisa B. Lee-Sherick, Madeline G. Huey, Elisabeth A. Lasater, Gregory D. Kirkpatrick, Michael A. Stashko, Weihe Zhang, Craig T. Jordan, Dmitri Kireev, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Neil P. Shah, Douglas K. Graham
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Research Article Oncology

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.

Authors

Katherine A. Minson, Catherine C. Smith, Deborah DeRyckere, Clara Libbrecht, Alisa B. Lee-Sherick, Madeline G. Huey, Elisabeth A. Lasater, Gregory D. Kirkpatrick, Michael A. Stashko, Weihe Zhang, Craig T. Jordan, Dmitri Kireev, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Neil P. Shah, Douglas K. Graham

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Figure 8

MRX-2843 mediates functional therapeutic effects in quizartinib-resistant FLT3-ITD xenograft models.

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MRX-2843 mediates functional therapeutic effects in quizartinib-resistan...
(A–D) Kaplan-Meier curves showing survival of NSG (A, B, and D) or NSGS (C) mice with orthotopic xenografts of MOLM-14 parental (A), MOLM-14:D835Y (B), or MOLM-14:F691L (C and D) cells, treated with MRX-2843, quizartinib (AC220), MRX-2843 vehicle (saline), or quizartinib vehicle (CD). (A) Disease burden was monitored in cohorts of mice, and treatment was initiated on day 22 after transplantation, when 7.2% ± 1.0% blasts were detected in the bone marrow. Treatment continued until day 145 after transplantation. Median survival was 121 days and 172.5 days for mice treated with MRX-2843 or quizartinib, respectively, compared with 36 days and 40 days for mice treated with MRX-2843 or quizartinib vehicle (n = 5 per group). (B) Disease burden was monitored in cohorts of mice, and treatment was initiated on day 26 after transplantation, when 6.8% ± 1.2% blasts were detected in the bone marrow. Treatment continued until conclusion of the study. Median survival was 94 days and 45 days after transplantation for mice treated with MRX-2843 or quizartinib, respectively, compared with 35.5 days and 36 days for mice treated with MRX-2843 or quizartinib vehicle (n ≥5 per group). (C) Treatment was initiated on day 28 after transplantation and continued until the conclusion of the study. Median survival was 87 days and 67 days after transplantation for mice treated with MRX-2843 or quizartinib, respectively, compared with 48 days and 55.5 days for mice treated with MRX-2843 or quizartinib vehicle (n ≥8 per group). (D) Disease burden was monitored in cohorts of mice, and treatment was initiated on day 38 after transplantation, when 49% ± 11% blasts were detected in the bone marrow. Treatment continued until 120 days after transplantation. Median survival was 87 days and 57 days for mice treated with MRX-2843 or quizartinib, respectively, compared with 44.5 days for mice treated with saline vehicle (n ≥4 per group). All P values in A–D were determined by log-rank test. CD, hydroxybutenyl-β-cyclodextrin; FLT3, FMS-like tyrosine kinase 3; ITD, internal tandem duplication; NSG, NOD-SCID-γ; NSGS, NOD-SCID-γ mice expressing Tg human cytokines.