TKI类药物在胃肠间质瘤临床应用中耐药机制的最新研究进展

The latest research progress of the mechanism of drug resistance to TKIs in clinical treatment of gastrointestinal stromal tumor

胃肠间质瘤(gastrointestinal stromal tumor,GIST)是胃肠道最常见的间叶源性肿瘤.绝大多数GIST的发病机制是受c-KIT(KIT proto-oncogene receptor tyrosine kinase)或血小板衍生生长因子受体α(platelet-derived growth factor receptor alpha,PDGFRA)基因的功能增益性突变驱动。原先GIST的临床治疗方案仅为手术切除,而以伊马替尼(imatinib)为代表的小分子酪氨酸激酶抑制剂(tyrosine kinase inhibtor,TKI)的问世则标志着GIST治疗进入靶向治疗的时代。TKI在GIST中取得了显著的临床疗效,目前已有多个TKI药物被批准用于临床治疗,极大地提高了GIST患者的生存期,但是紧随而来的耐药问题是一个亟需解决的难点。目前已明确GIST对TKI耐药的主要原因是c-KIT或PDGFRA不同外显子的继发突变。然而,即使是带有相同外显子突变的GIST患者,其对TKI的反应仍存在较大差异,暗示着可能存在与c-KIT和PDGFRA同时作用的其它机制。得益于分子生物学技术(如CRISPR基因编辑技术)的发展成熟和应用,对TKI类药物耐药和敏感的GIST之间的遗传学差异越来越清晰,越来越多的新机制被阐明。本文就GIST对临床常用的TKI类药物耐药机制的最新研究进展做一梳理。

Gastrointestinal stromal tumor(GIST)is the most common mesenchymal tumor of the gastrointestinal tract.The pathogenesis of most GIST is driven by the gain-of-function mutations of KIT proto-oncogene receptor tyrosine kinase(c-KIT)or platelet-derived growth factor receptor alpha(PDGFRA)gene.The original clinical treatment for GIST was surgical resection only.With the advent of tyrosine kinase inhibitors(TKIs)represented by imatinib,GIST therapy has entered the era of targeted therapy.TKIs have achieved significant clinical efficacy in GIST treatment.To date,several TKI drugs have been approved for clinical application,which has greatly improved the survival time of GIST patients,but the ensuing drug resistance problem is a difficult problem that requires an urgent solution.Currently,it has been confirmed that the main reason for drug resistance to TKI in GIST is the secondary mutation of different exons of c-KIT or PDGFRA.However,even GIST patients with the same exon mutation still reacts very differently to TKIs,suggesting that there may be other mechanisms acting in parallel with c-KIT and PDGFRA.Thanks to the development and application of molecular biological technologies such as CRISPR gene editing technology,the genetic differences between TKI drug resistant and sensitive GIST are becoming clearer and clearer,and many more new mechanisms have been identified.This paper summarizes the latest research progress of the mechanism of drug resistance to the most commonly used TKIs in the clinical treatment of GIST.