A narrative review of imatinib-resistant gastrointestinal stromal tumors.
A narrative review of imatinib-resistant gastrointestinal stromal tumors.
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DOI：
10.21037/gist-21-10
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发表时间：
2021-10-01
期刊：
影响因子：
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通讯作者：
Nguyen, Vy Truong Thuy
中科院分区：
文献类型：
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作者：
Hayashi, Yujiro;Nguyen, Vy Truong Thuy
目的：综述对伊马替尼耐药的胃肠道间质瘤(GIST)发病机制的研究。背景：GIST是人类最常见的胃肠道间充质肿瘤和最常见的肉瘤。GIST被认为起源于Cajal间质细胞(ICC)、胃肠道中的起搏细胞和神经调制细胞，以及“成纤维细胞”样细胞，这是肠壁的另一种间质细胞，也被称为端粒细胞或血小板衍生生长因子-α(PDGFRA)阳性细胞。大多数GIST在KIT或PDGFRA中都存在功能获得突变，这些功能获得突变是相互排斥的，最常见的是杂合性突变。GIST对KIT/PDGFRA酪氨酸激酶抑制剂(TKI)伊马替尼有效，伊马替尼是治疗晚期和转移性GIST的标准一线药物。然而，尽管有初步的临床益处，单用伊马替尼并不能根除GIST，而且90%以上的GIST对伊马替尼耐药。虽然第二代和第三代TKI已经开发出来并目前正在临床使用，但由于出现了具有耐药突变的克隆，它们无法治愈难治性和转移性GIST。根除耐药的GIST将治愈难治性GIST患者。几种机制可能导致难治性GIST。这些机制是KIT和/或PDGFRA的继发性突变，酪氨酸激酶的交替激活，GIST的干细胞和细胞静止，细胞静止是一种可逆的非增殖状态，细胞保持重新进入细胞增殖的能力。方法：我们回顾了我们目前治疗晚期和难治性GIST的最佳治疗方法。结论：该综述探索了对抗耐药GIST的新的和潜在的治疗方法。
Objective: Review the studies that investigate the mechanisms underlying imatinib-resistant gastrointestinal stromal tumors (GIST).Background: GIST are the most common mesenchymal tumors of the gastrointestinal (GI) tract and the most common sarcoma in humans. GIST are thought to be arise from interstitial cells of Cajal (ICC), pacemaker and neuromodulator cells in the GI tract, as well as "fibroblast"-like cells, which are another type of interstitial cells of the gut wall and also known as telocyte or platelet-derived growth factor-alpha (PDGFRA)-positive cells. The majority of GIST harbor gain-of-function mutations in either KIT or PDGFRA, and these gain-of-function mutations are mutually exclusive and most often heterozygous. GIST are responsive to the KIT/PDGFRA tyrosine kinase inhibitor (TKI), imatinib, the standard first-line drug for advanced and metastatic GIST. However, imatinib alone does not eradicate GIST despite an initial clinical benefit, and more than 90% of GIST harbor imatinib-resistance. Although second and third-generation TKIs have been developed and are currently in clinical use, they are not curative for refractory and metastatic GIST due to the emergence of clones with drug-resistant mutations. Eradication of drug-resistant GIST will cure patients with refractory GIST. Several mechanisms may contribute to refractory GIST. These mechanisms are secondary mutations in KIT and/or PDGFRA, alternative activation of tyrosine kinases, stem cells for GIST and cellular quiescence, a reversible nonproliferating state in which cells retain the ability to reenter cell proliferation.Methods: We review our current optimal treatment approach for managing patients with advanced and refractory GIST.Conclusions: This review explores the novel and potential therapeutic approaches to combat drug-resistant GIST.