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

  • JCI Insight. 2016 Mar;1(3):e85630. doi: 10.1172/jci.insight.85630.
Katherine A Minson  1 ,  Catherine C Smith  2 ,  Deborah DeRyckere  1  3 ,  Clara Libbrecht  4 ,  Alisa B Lee-Sherick  4 ,  Madeline G Huey  1 ,  Elisabeth A Lasater  2 ,  Gregory D Kirkpatrick  4 ,  Michael A Stashko  5 ,  Weihe Zhang  5 ,  Craig T Jordan  6 ,  Dmitri Kireev  5 ,  Xiaodong Wang  5 ,  Stephen V Frye  5  7 ,  H Shelton Earp  7  8 ,  Neil P Shah  2 ,  Douglas K Graham  1  3
Affiliations
  • 1. Aflac Cancer Center of Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA.
  • 2. UCSF, Department of Medicine, San Francisco, California, USA.
  • 3. Winship Cancer Institute, Emory University, Atlanta, GA, USA.
  • 4. University of Colorado, Department of Pediatrics, Aurora, Colorado, USA.
  • 5. University of North Carolina at Chapel Hill, Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
  • 6. University of Colorado, Department of Medicine, Aurora, Colorado, USA.
  • 7. UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 8. University of North Carolina at Chapel Hill, Department of Medicine, Chapel Hill, North Carolina, USA.
PMID: 27158668 DOI: 10.1172/jci.insight.85630
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.

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