title: Selective FLT3 inhibition of FLT3-ITD+ acute myeloid leukaemia resulting in secondary D835Y mutation: a model for emerging clinical resistance patterns.
abstract: 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.
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Moore
authors.forename: A
authors.initials: A
authors.lastname: Faisal
authors.forename: D
authors.initials: D
authors.lastname: Gonzalez de Castro
authors.forename: V
authors.initials: V
authors.lastname: Bavetsias
authors.forename: C
authors.initials: C
authors.lastname: Sun
authors.forename: B
authors.initials: B
authors.lastname: Atrash
authors.forename: M
authors.initials: M
authors.lastname: Valenti
authors.forename: A
authors.initials: A
authors.lastname: de Haven Brandon
authors.forename: S
authors.initials: S
authors.lastname: Avery
authors.forename: D
authors.initials: D
authors.lastname: Mair
authors.forename: F
authors.initials: F
authors.lastname: Mirabella
authors.forename: J
authors.initials: J
authors.lastname: Swansbury
authors.forename: A D J
authors.initials: AD
authors.lastname: Pearson
authors.forename: P
authors.initials: P
authors.lastname: Workman
authors.forename: J
authors.initials: J
authors.lastname: Blagg
authors.forename: F I
authors.initials: FI
authors.lastname: Raynaud
authors.forename: S A
authors.initials: SA
authors.lastname: Eccles
authors.forename: S
authors.initials: S
authors.lastname: Linardopoulos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D001557:Benzenesulfonates / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D000077157:Sorafenib; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C551619:3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo(4,5-b)pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole; D001557:Benzenesulfonates; D052160:Benzothiazoles; D007093:Imidazoles; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011799:Quinazolines; D009536:Niacinamide; C544967:quizartinib; D000077157:Sorafenib; C464670:tandutinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases