Florou Vaia, Trent Jonathan C, Wilky Breelyn A
Department of Medicine, Division of Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Department of Medicine, Division of Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Discov Med. 2019 Nov-Dec;28(155):267-276.
Gastrointestinal stromal tumors (GISTs) are rare soft tissue sarcomas of the gastrointestinal tract, with most carrying conserved driver mutations in the tyrosine kinase receptors KIT or PDGFRα. The use of targeted therapy against these mutations in GISTs is one of the most successful examples of precision medicine in solid tumors, beginning in 2002 with the development of imatinib, a small molecule tyrosine kinase inhibitor (TKI) of KIT. In recent years, much progress has been made in understanding the molecular mechanisms of GISTs while unveiling their genetic heterogeneity. Since development of secondary mutations leads to imatinib resistance, the majority of research efforts have focused on identification of novel inhibitors to improve outcomes in imatinib-resistant GISTs. Sunitinib and regorafenib are two TKIs with demonstrated activity after failure of imatinib, which led to the U.S. FDA approval. Pivotal phase 3 clinical trials are ongoing with two novel agents, avapritinib and ripretinib, based on their remarkable activities in the 4th or greater line settings in phase 1/2 studies of these drugs. In this review, we will outline the remarkable diversity of genetic mutations in GISTs, and review the evidence for treatment options of genomic medicine in locally advanced or metastatic gastrointestinal stromal tumors.
胃肠道间质瘤（GISTs）是胃肠道罕见的软组织肉瘤，大多数携带酪氨酸激酶受体KIT或PDGFRα的保守驱动基因突变。针对GISTs中这些突变的靶向治疗是实体瘤精准医学最成功的例子之一，始于2002年伊马替尼的研发，伊马替尼是一种KIT的小分子酪氨酸激酶抑制剂（TKI）。近年来，在了解GISTs的分子机制并揭示其基因异质性方面取得了很大进展。由于继发性突变的产生会导致伊马替尼耐药，大多数研究工作都集中在寻找新型抑制剂以改善伊马替尼耐药GISTs的治疗效果。舒尼替尼和瑞戈非尼是两种在伊马替尼治疗失败后显示出活性的TKI，这两种药物已获得美国食品药品监督管理局（FDA）批准。基于两种新型药物阿伐替尼和瑞派替尼在1/2期研究的四线及以上治疗中的显著活性，关键的3期临床试验正在进行。在这篇综述中，我们将概述GISTs基因突变的显著多样性，并回顾局部晚期或转移性胃肠道间质瘤基因组医学治疗选择的证据。
