The dual MEK/FLT3 inhibitor E6201 exerts cytotoxic activity against acute myeloid leukemia cells harboring resistance-conferring FLT3 Mutations

Weiguo Zhang, Gautam Borthakur, Chen Gao, Ye Chen, Hong Mu, Vivian R. Ruvolo, Kenichi Nomoto, Nanding Zhao, Marina Konopleva, Michael Andreeff

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

FMS-like tyrosine kinase 3 (FLT3) inhibition has elicited encouraging responses in acute myeloid leukemia (AML) therapy. Unfortunately, unless combined with a bone marrow transplant, disease relapse is frequent. In addition to the acquired point mutations in the FLT3 kinase domain that contribute to FLT3 inhibitor resistance, MEK/ERK signaling is persistently activated in AML cells even when FLT3 phosphorylation is continually suppressed. Thus, concomitant targeting of FLT3 and MAPK may potentially exert synergistic activity to counteract the resistance of AML cells to FLT3-targeted therapy. In this study, we investigated the antileukemia activity of aMEK1 and FLT3 dual inhibitor, E6201, in AML cells resistant to FLT3 inhibition.We found that E6201 exerted profound apoptogenic effects on AML cells harboring resistance-conferring FLT3 mutations. This activity appeared to be p53 dependent, and E6201- induced cytotoxicity was retained under hypoxic culture conditions and during coculture with mesenchymal stem cells that mimic the AML microenvironment. Furthermore, E6201 markedly reduced leukemia burden and improved the survival of mice in a human FLT3-mutated AML model. Collectively, our data provide a preclinical basis for the clinical evaluation of E6201 in AML patients harboring FLT3 mutations, including those who relapse following FLT3-targeted monotherapy.

Original languageEnglish (US)
Pages (from-to)1528-1537
Number of pages10
JournalCancer Research
Volume76
Issue number6
DOIs
StatePublished - Mar 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Flow Cytometry and Cellular Imaging Facility
  • Research Animal Support Facility
  • Cytogenetics and Cell Authentication Core

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