基因组ATP结合口袋/激活环突变在胃肠道管道瘤中:激酶抑制剂逃逸的新兴机制
Thomas Mühlenberg1,2, Johanna Falkenhorst1,2, Tom Schulz3,4
1Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
概括
在胃肠道 stromal 瘤 (GISTs) 中对ripretinib的耐药性是由ATP结合口袋 (AP) 中新的KIT突变驱动的,这些突变与现有的激活循环 (AL) 突变发生. 这些AP/AL基因型限制了高级GIST的治疗选择.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 胃肠道 stromal 瘤 (GISTs) 中的伊马替尼抗性主要是由二次 KIT 突变驱动的,这在治疗中构成了重大挑战.
- 虽然KIT抑制剂表现出一些活性,但它们在以后的治疗线,如ripretinib的第四线治疗中所带来的益处仍然有限,耐药性机制尚未完全理解.
研究的目的:
- 研究GISTs患者对ripretinib耐药性的分子机制.
- 为了识别与ripretinib折射性相关的新型KIT突变.
主要方法:
- 基因组测序KIT耐药突变的GIST病变从25个患者对ripretinib不耐药.
- 使用细胞系和in silico模型对抗性基因型的验证和表征.
主要成果:
- 在ripretinib上进展的GIST显示了ATP结合口袋 (AP) 中的二次KIT突变的丰富,通常与先前存在的激活循环 (AL) 突变同时发生,形成高度耐药的AP/AL基因型.
- 这些AP/AL突变在ripretinib前的时代是罕见的,但构成了对ripretinib耐药GIST的二次KIT突变的50%.
- 实验室模型证实,AP/AL突变是对ripretinib的主要逃脱机制,虽然ripretinib和sunitinib等组合抑制了一些耐药克隆,但它们对AP/AL基因型无效.
结论:
- 即使使用多种疗法,KIT仍然是高级GIST的关键瘤驱动因素.
- 在ripretinib治疗后出现KIT AP/AL突变,凸显了对新型治疗策略和下一代KIT抑制剂的需求.
- 组合疗法可能有助于抑制二次KIT突变的抗性,但需要新的方法来克服AP/AL介导的抗性.
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