title: 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.affiliation: Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Minson
authors.affiliation: UCSF, Department of Medicine, San Francisco, California, USA.
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Smith
authors.affiliation: Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA.|Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: DeRyckere
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, Colorado, USA.
authors.forename: Clara
authors.initials: C
authors.lastname: Libbrecht
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, Colorado, USA.
authors.forename: Alisa B
authors.initials: AB
authors.lastname: Lee-Sherick
authors.affiliation: Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA.
authors.forename: Madeline G
authors.initials: MG
authors.lastname: Huey
authors.affiliation: UCSF, Department of Medicine, San Francisco, California, USA.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Lasater
authors.affiliation: University of Colorado, Department of Pediatrics, Aurora, Colorado, USA.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirkpatrick
authors.affiliation: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Stashko
authors.affiliation: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
authors.forename: Weihe
authors.initials: W
authors.lastname: Zhang
authors.affiliation: University of Colorado, Department of Medicine, Aurora, Colorado, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kireev
authors.affiliation: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.|UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Frye
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|University of North Carolina at Chapel Hill, Department of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.affiliation: UCSF, Department of Medicine, San Francisco, California, USA.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.affiliation: Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA.|Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Graham