在结肠直肠癌中获得对EGFR锁的耐药性的分子演变
Luis A Diaz1, Richard T Williams, Jian Wu
1Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21287, USA. ldiaz1@jhmi.edu
罕见的KRAS突变在结直肠瘤中已经存在,并在EGFR阻塞治疗期间出现. 在血液中检测这些KRAS突变可以预测对抗EGFR抗体的获得性耐药性.
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:
- 最初对EGFR阻塞敏感的结肠直肠瘤通常会发展出耐药性.
- 获得抗EGFR抗体耐药性的机制尚不清楚.
- 与小分子抑制剂不同,抗体基EGFR阻断的耐药性缺乏明确的遗传标.
研究的目的:
- 为了调查预先存在的KRAS突变驱动对EGFR阻塞的获得性耐药性的假设.
- 为了确定是否可以检测到突变的KRAS DNA在接受抗EGFR抗体治疗的患者循环中.
- 探索KRAS突变的非侵入性检测对预测耐药性的临床实用性.
主要方法:
- 在接受panitumumab的患者中,分析循环瘤DNA (ctDNA) 检测KRAS突变.
- 在血清中使用分子技术检测KRAS突变.
- 数学建模以评估突变的时间和克隆扩张.
主要成果:
- 在38%最初患有KRAS野生型瘤的患者的血清中检测到突变KRASDNA.
- 在一些患者中发现了多个不同的KRAS突变.
- 突变的出现通常发生在治疗5-6个月之间,这表明已经存在的子克隆.
结论:
- KRAS突变的出现是结直肠癌中对EGFR阻塞获得的耐药性的关键媒介.
- 在血清中非侵入性检测KRAS突变是可行的,可以预测耐药性.
- 这些发现解释了对向疗法的耐药性可重复的发展.
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