Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns.
Data(s) |
01/07/2012
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Resumo |
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. |
Identificador | |
Idioma(s) |
eng |
Direitos |
info:eu-repo/semantics/restrictedAccess |
Fonte |
Moore , A S , Faisal , A , Gonzalez de Castro , D , Bavetsias , V , Sun , C , Atrash , B , Valenti , M , de Haven Brandon , A , Avery , S , Mair , D , Mirabella , F , Swansbury , J , Pearson , A D , Workman , P , Blagg , J , Raynaud , F I , Eccles , S A & Linardopoulos , S 2012 , ' Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns. ' Leukemia , vol 26 , no. 7 , pp. 1462-1470 . DOI: 10.1038/leu.2012.52 |
Palavras-Chave | #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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article |