Department of Medicine, Bergonié Institute, Bordeaux.
Expert Opin Pharmacother. 2021 Mar;22(4):439-447. doi: 10.1080/14656566.2020.1828346. Epub 2020 Dec 14.
90% of gastrointestinal stromal tumors (GISTs) harbor an activating mutation in the or oncogene, and these are known to confer imatinib sensitivity.
The author reviews the data regarding the current management of GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical development and provides his unique perspectives on the subject matter.
Several studies have shown that the response to imatinib in GIST patients mainly depends on the mutational status of or . Moreover, most, if not all, patients treated with imatinib for advanced GIST will develop a secondary progressive disease under the treatment. In most cases, such progressions are the result of acquired resistance due to the occurrence of secondary mutations, especially in GISTs with primary exon 11 mutations. Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. Clearly, better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors such as avapritinib and ripretinib will provide new individualized therapeutic strategies for GIST patients.
90%的胃肠道间质瘤（GIST）存在 或 癌基因的激活突变，这些突变已知可导致伊马替尼敏感性。
作者回顾了关于 GIST 当前管理、伊马替尼耐药机制以及目前临床开发的新药的数据，并就这一主题提供了自己独特的观点。
几项研究表明，GIST 患者对伊马替尼的反应主要取决于 或 的突变状态。此外，接受伊马替尼治疗的晚期 GIST 患者，大多数（如果不是全部）在治疗下会出现继发性进行性疾病。在大多数情况下，这种进展是由于继发性 突变的发生而导致的获得性耐药，特别是在具有原发性外显子 11 突变的 GIST 中。舒尼替尼和瑞戈非尼是多种酪氨酸激酶的抑制剂，包括 KIT、PDGFRα、PDGFRβ 和 VEGFRs，分别被批准用于治疗伊马替尼和伊马替尼/舒尼替尼耐药的 GIST 患者。显然，更好地了解导致伊马替尼耐药的分子机制以及开发阿伐普利替尼和 ripretinib 等新型广谱酪氨酸激酶抑制剂将为 GIST 患者提供新的个体化治疗策略。
