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酪氨酸激酶抑制剂治疗晚期胃肠道间质瘤

Author
Jeffrey Morgan, MD
Section Editors
Kenneth K Tanabe, MD
Robert Maki, MD, PhD
Deputy Editor
Diane MF Savarese, MD
Translators
王临润, 主任药师

引言

在过去的30年间，在如何发现和分类侵犯胃肠(gastrointestinal, GI)道的间质或间充质肿瘤方面已获得了长足的发展。一个重大的突破是发现这些肿瘤[现在称为胃肠道间质瘤(gastrointestinal stromal tumor, GIST)]几乎均会表达CD117抗原。胃肠道出现的其他梭形细胞肿瘤通常为CD117阴性，这些肿瘤类似于遍布身体其他部位的软组织肿瘤，包括脂肪瘤、神经鞘瘤、血管瘤、普通平滑肌瘤与恶性的平滑肌瘤(即，平滑肌肉瘤)[1]。

CD117分子是KIT(c-kit)受体的一部分，而KIT受体是一种膜酪氨酸激酶(tyrosine kinase, TK)，为KIT原癌基因的产物。在80%的病例中，KIT过表达是KIT原癌基因活化突变的结果。虽然大部分GIST是KIT阳性，但是一些KIT阴性的GIST在一种相关的TK受体即血小板衍生生长因子受体α(platelet-derived growth factor receptor alpha, PDGFRA)上存在活化突变。当前的观点是绝大多数的胃肠道间充质肿瘤都属于GIST；可通过KIT免疫反应性或者KIT或PDGFRA中存在活化突变来确定这些肿瘤。 (参见“胃肠道间叶源性肿瘤(包括胃肠间质瘤)的流行病学、分类、临床表现、预后特征及诊断性检查”，关于‘分类及分子发病机制’一节)

2000年之前，对于不能手术切除的GIST或转移性GIST没有已知有效的疗法。长期以来人们都觉得，相比于其他部位的软组织肉瘤，胃肠道肉瘤对化疗的反应率较低，提示这些肿瘤对化疗具有较高的原发性耐药率[2-4]。

KIT或PDGFRA的突变激活可刺激这些癌细胞的生长，这一发现彻底改变了GIST的治疗。这使得多种TK受体的小分子抑制剂成为有效的全身性疗法。原型药伊马替尼(甲磺酸伊马替尼)最初被批准用于治疗慢性髓系白血病(chronic myeloid leukemia, CML)，CML是一种分子重排导致TK异常的疾病。 (参见“慢性髓系白血病慢性期的初始治疗”)

随后不断有证据表明，使用伊马替尼对GIST进行分子靶向治疗同样能获得显著、快速且持续的临床获益。KIT或PDGFRA受体的磷酸化和激活需要三磷酸腺苷(adenosine triphosphate, ATP)结合口袋，而这些药物能通过与ATP结合口袋结合而阻断KIT或PDGFRA信号传递。其他酪氨酸激酶抑制剂(TK inhibitor, TKI)已被证实可以阻断多个TK靶点，包括KIT(被称为多靶点TKI)。一些数据提示使用伊马替尼治疗的GIST患者获得良好临床结局与其抗GIST免疫应答相关[5]。

                           

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Literature review current through: 2017-06 . | This topic last updated: 2016-06-23.
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