CLIN CANCER RES:Avapritinib治疗胃肠道间质瘤

2019-01-27 MedSci MedSci原创

胃肠道间质瘤(GIST)通常用酪氨酸激酶抑制剂(TKI)治疗。大多数晚期GIST患者由于获得继发性KIT突变而最终对TKI产生抗性,而原发性抗性主要由PDGFR A p.D842V突变引起。CLIN CANCER RES近期发表了一篇文章,在携带不同KIT突变的三种患者来源的异种移植物(PDX)GIST模型中研究avapritinib(一种有效且高选择性的突变KIT和PDGFRA抑制剂)的活性,以

肠道间质瘤(GIST)通常用酪氨酸激酶抑制剂(TKI)治疗。大多数晚期GIST患者由于获得继发性KIT突变而最终对TKI产生抗性,而原发性抗性主要由PDGFR A p.D842V突变引起。CLIN CANCER RES近期发表了一篇文章,在携带不同KIT突变的三种患者来源的异种移植物(PDX)GIST模型中研究avapritinib(一种有效且高选择性的突变KIT和PDGFRA抑制剂)的活性,以及对标准TKI治疗的不同的敏感性。

作者用NMRI nu / nu小鼠(n = 93)建立三种模型,分别存在KIT外显子11 + 17(UZLX-GIST9 KIT 11 + 17),外显子11(UZLX-GIST3 KIT 11)或外显子9(UZLX-GIST2B KIT9)突变。作者在不同模型中比较了avapritinib与其他药物对肿瘤的抑制情况。包括:avapritinib(10和30 mg / kg /每日一次)与伊马替尼(50 mg / kg / bid)或瑞格非尼(30 mg / kg /每日一次; UZLX-GIST9 KIT11 + 17模型); avapritinib(10,30,100 mg / kg /每日一次)与伊马替尼[UZLX-GIST3 KIT11 模型]; avapritinib(10,30,60 mg / kg /每日一次)与伊马替尼(50,100 mg / kg /每日两次)或舒尼替尼(40 mg / kg /每日一次; UZLX-GIST2B KIT9模型)。研究结果表明,在所有模型中,avapritinib均可以导致肿瘤体积减小,显着抑制增殖,并减少KIT信号传导。在两个模型中,avapritinib导致明显的组织学反应,细胞凋亡增加和MAPK磷酸化抑制。Avapritinib 与标准剂量的伊马替尼相比表现出更佳(UZLX-GIST9 KIT 11 + 17和-GIST2B KIT 9)或相似(UZLX-GIST3 KIT 11)的抗肿瘤活性。在UZLX-GIST9 KIT 11 + 17模型中,avapritinib的抗肿瘤作用明显优于伊马替尼或瑞格非尼。

文章最后认为,Avapritinib在GIST PDX模型中具有显着的抗肿瘤活性。这些数据为Avapritinib治疗GIST患者的临床试验提供了强有力的支持。

原始出处:

Yemarshet K. Gebreyohannes, Agnieszka Wozniak, et al. Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors. CLIN CANCER RES. January 2019 doi: 10.1158/1078-0432.CCR-18-1858

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    2020-01-08 hxzhang
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    2019-08-13 hbwxf
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