School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.
Priority Research Centre for Cancer Research, Innovation & Translation, Faculty of Health & Medicine, Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
Int J Mol Sci. 2018 Oct 16;19(10):3198. doi: 10.3390/ijms19103198.
The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30⁻35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a 'dual mutation' (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML.
酪氨酸激酶编码基因中反复出现的驱动突变的鉴定,导致了针对特定分子的治疗策略的发展,旨在改善急性髓系白血病(AML)患者的预后。受体酪氨酸激酶 FLT3 是 AML 中最常见的突变基因,在近膜区(FLT3-ITD)内有内部串联重复或酪氨酸激酶区(FLT3-TKD)的错义突变,在 AML 患者中有 30⁻35%在诊断时存在。FLT3 酪氨酸激酶是一个既定的驱动突变和预后不良的标志物,已成为一个有吸引力的治疗靶点,因此鼓励开发 FLT3 酪氨酸激酶抑制剂(TKIs)。然而,FLT3 抑制的治疗益处,特别是作为单一疗法,常常导致治疗耐药和疾病复发。通常,FLT3 抑制剂耐药是通过基因中的继发病变的出现,特别是在第二酪氨酸激酶结构域(TKD)中的残基 Asp835(D835)形成“双重突变”(ITD-D835)。单个 FLT3-ITD 和 FLT3-TKD 突变影响独立的信号级联;然而,对于每个特定的 FLT3 突变控制哪些不同的信号通路,特别是在携带双重 ITD-D835 突变的患者背景下,知之甚少。这篇综述全面分析了已知的每个特定的 FLT3 突变所失调的离散和协同信号通路,以及具有最有前途的持久和个性化治疗方法的治疗方法,以改善 FLT3 突变 AML 的治疗。