Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns.

A.S. Moore, A. Faisal, D. Gonzalez de Castro, V. Bavetsias, C. Sun, B. Atrash, M. Valenti, A. de Haven Brandon, S. Avery, D. Mair, F. Mirabella, J. Swansbury, A.D. Pearson, P. Workman, J. Blagg, F.I. Raynaud, S.A. Eccles, S. Linardopoulos

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88 Citations (Scopus)


Acquired resistance to selective FLT3 inhibitors is an emerging clinical problem in the treatment of FLT3-ITD(+) acute myeloid leukaemia (AML). The paucity of valid pre-clinical models has restricted investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. We generated selective FLT3 inhibitor-resistant cells by treating the FLT3-ITD(+) human AML cell line MOLM-13 in vitro with the FLT3-selective inhibitor MLN518, and validated the resistant phenotype in vivo and in vitro. The resistant cells, MOLM-13-RES, harboured a new D835Y tyrosine kinase domain (TKD) mutation on the FLT3-ITD(+) allele. Acquired TKD mutations, including D835Y, have recently been identified in FLT3-ITD(+) patients relapsing after treatment with the novel FLT3 inhibitor, AC220. Consistent with this clinical pattern of resistance, MOLM-13-RES cells displayed high relative resistance to AC220 and Sorafenib. Furthermore, treatment of MOLM-13-RES cells with AC220 lead to loss of the FLT3 wild-type allele and the duplication of the FLT3-ITD-D835Y allele. Our FLT3-Aurora kinase inhibitor, CCT137690, successfully inhibited growth of FLT3-ITD-D835Y cells in vitro and in vivo, suggesting that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML.
Original languageEnglish
Pages (from-to)1462-1470
Number of pages9
Issue number7
Publication statusPublished - Jul 2012


  • Animals
  • Apoptosis
  • Aurora Kinases
  • Benzenesulfonates
  • Benzothiazoles
  • Blotting, Western
  • Cell Cycle
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Imidazoles
  • Leukemia, Myeloid, Acute
  • Mice
  • Mice, Nude
  • Mutation
  • Niacinamide
  • Phenylurea Compounds
  • Piperazines
  • Protein Kinase Inhibitors
  • Protein-Serine-Threonine Kinases
  • Pyridines
  • Quinazolines
  • Tandem Repeat Sequences
  • Tumor Cells, Cultured
  • fms-Like Tyrosine Kinase 3


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