突变
突变
酪氨酸激酶
酪氨酸激酶抑制剂
生物
分子生物学
医学
遗传学
基因
信号转导
癌症
作者
Theodore C. Tarver,Jason E. Hill,Leena Rahmat,Alexander E. Perl,Erkut Bahceci,Kenichi Mori,Catherine C. Smith
出处
期刊:Blood Advances
[Elsevier BV]
日期:2020-02-10
卷期号:4 (3): 514-524
被引量:68
标识
DOI:10.1182/bloodadvances.2019000919
摘要
Abstract Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at <200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.
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