■回顾研究伊马替尼耐药胃肠道间质瘤(GIST)潜在机制的研究。
■GIST是人类最常见的胃肠道(GI)间充质肿瘤和最常见的肉瘤。GIST被认为是由Cajal(ICC)的间质细胞产生的,胃肠道中的起搏器和神经调质细胞,以及“成纤维细胞”样细胞,它们是另一种类型的肠壁间质细胞,也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中都有功能获得性突变,这些功能获得性突变是相互排斥的,并且通常是杂合的。GIST对KIT/PDGFRA酪氨酸激酶抑制剂(TKI)有反应,伊马替尼,晚期和转移性GIST的标准一线药物。然而,单用伊马替尼并不能根除GIST,尽管有最初的临床获益,超过90%的GIST对伊马替尼耐药。虽然第二代和第三代TKIs已经开发出来,目前正在临床使用,由于出现了具有耐药突变的克隆,它们不能治愈难治性和转移性GIST.根除耐药GIST将治愈难治性GIST患者。几种机制可能有助于难治性GIST。这些机制是KIT和/或PDGFRA的次级突变,酪氨酸激酶的替代激活,GIST和细胞静止的干细胞,一种可逆的非增殖状态,其中细胞保留重新进入细胞增殖的能力。
■我们回顾了目前治疗晚期和难治性GIST患者的最佳治疗方法。
■这篇综述探讨了对抗耐药GIST的新的和潜在的治疗方法。
UNASSIGNED: Review the studies that investigate the mechanisms underlying imatinib-resistant gastrointestinal stromal tumors (GIST).
UNASSIGNED: 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.
UNASSIGNED: We
review our current optimal treatment approach for managing patients with advanced and refractory GIST.
UNASSIGNED: This
review explores the novel and potential therapeutic approaches to combat drug-resistant GIST.