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

• Type of Material: Article
• Authors: Katherine Minson, Emory University; Catherine C. Smith, University of California San Francisco; Deborah DeRyckere, Emory University; Clara Libbrecht, University of Colorado; Alisa B. Lee-Sherick, University of Colorado; Madeline G. Huey, Childrens Healthcare Atlanta; Elisabeth A. Lasater, University of California San Francisco; Gregory D. Kirkpatrick, University of Colorado; Michael A. Stashko, University of North Carolina Chapel Hill; Weihe Zhang, University of North Carolina Chapel Hill; Craig T. Jordan, University of Colorado; Dmitri Kireev, University of North Carolina Chapel Hill; Xiaodong Wang, University of North Carolina Chapel Hill; Stephen C. Frye, University of North Carolina Chapel Hill; H. Shelton Earp, University of North Carolina Chapel Hill; Neil P. Shah, University of California San Francisco; Douglas Graham, Emory University
• Language: English
• Date: 2016-03-17
• Publisher: American Society for Clinical Investigation Inc
• Publication Version: Final Published Version
• Copyright Statement: © 2016, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.85630
• Title of Journal or Parent Work: JCI Insight
• Volume: 1
• Issue: 3
• Start Page: e85630
• End Page: e85630
• Grant/Funding Information: This work was supported by grants from the NIH (2T32CA082086-11, to K.A. Minson and 1R01CA137078, to D.K. Graham); the Leukemia and Lymphoma Society Translation Research Program (to D.K. Graham); the University of North Carolina Cancer Research Fund; and federal funds from the National Cancer Institute’s Experimental Therapeutics (NExT) program, NIH, under contract HHSN261200800001E.
• Keywords: RCS RAT; RECEPTOR TYROSINE KINASE; PHASE; GENE; THERAPEUTIC TARGET; MER; AXL; INTERNAL TANDEM DUPLICATION; Science & Technology; CRENOLANIB; Medicine, Research & Experimental; Research & Experimental Medicine; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology

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.