Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Constitutive activation of cKIT kinase mediated signaling pathway is essential for the tumorigenesis of GISTs.^1,2 cKIT kinase is a type III receptor tyrosine kinase that upon stem cell factor (SCF) stimulation will activate downstream signaling pathways such as RAS/RAF/ERK and PI3K/AKT to regulate the cell proliferation, survival, apoptosis, and differentiation. Approximately 75% GISTs harbor oncogenic gain-of-function KIT gene mutations that mimic the SCF-induced constitutive signaling pathway activation.³ Currently, over 20 different functional mutations have been identified in the clinic.⁴ Most primary mutations such as L576P and V559D/A/G mutants occur in the extracellular domain and juxtamembrane (JM) domain.^5–7 Secondary mutations are induced by drug treatment and usually located at the ATP binding pocket such as cKIT V654A and the gatekeeper mutant T670I, or at the activation loop such as D816V/H, N822K, and A829P .^8–10

中文翻译：

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阿西替尼克服了多种伊马替尼耐药 cKIT 突变，包括胃肠道间质瘤中的守门人突变 T670I

胃肠道间质瘤（GISTs）是胃肠道最常见的间充质肿瘤。cKIT 激酶介导的信号通路的组成性激活对于 GIST 的肿瘤发生至关重要。^1,2 cKIT 激酶是一种 III 型受体酪氨酸激酶，在干细胞因子 (SCF) 刺激下会激活下游信号通路，例如 RAS/RAF/ERK 和 PI3K/AKT，从而调节细胞增殖、存活、凋亡和分化。大约 75% 的 GIST 具有致癌的功能获得性 KIT 基因突变，这些突变模拟 SCF 诱导的组成型信号通路激活。³目前，临床上已鉴定出超过 20 种不同的功能突变。⁴大多数初级突变如 L576P 和 V559D/A/G 突变体发生在细胞外结构域和近膜 (JM) 结构域。^5-7二次突变由药物治疗诱导，通常位于 ATP 结合口袋，如 cKIT V654A 和守门突变体 T670I，或位于激活环，如 D816V/H、N822K 和 A829P。^8–10