双重PIK3CA突变增加了对PI3Kα抑制剂的致癌性和敏感性
Neil Vasan1,2,3, Pedram Razavi1,2, Jared L Johnson3
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
概括
在癌症中多个PIK3CA突变,特别是双重突变,增强PI3K通路活性. 这些发现表明,双重PIK3CA突变的患者可能从PI3Kα抑制剂治疗中获益更多.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 激活PIK3CA的突变在乳腺癌中很常见.
- 酸三酶α (PI3Kα) 抑制剂已被批准用于治疗某些癌症.
- 了解PIK3CA突变状态对于预测治疗反应至关重要.
研究的目的:
- 调查多个PIK3CA突变的流行率和功能影响.
- 确定对PI3Kα抑制剂敏感性的决定因素.
- 为了比较单个和双个PIK3CA突变的影响.
主要方法:
- 对PIK3CA突变癌症样本的基因组分析.
- 生物化学测定以评估PI3K活动和信号.
- 对细胞增殖和瘤生长的评估.
- 基于突变状态的PI3Kα抑制剂的敏感性比较.
主要成果:
- 分析的癌症中有12-15%具有多个PIK3CA突变,主要是同一基因基因 (cis) 的双重突变.
- 双重PIK3CA突变导致PI3K活性增加,下游信号增强,细胞增殖和瘤生长加速.
- 生物化学机制包括受损的p110α/ p85α结合和增加的p110α膜脂结合.
- 与单个热点突变相比,双重PIK3CA突变与PI3Kα抑制剂的敏感性增加有关.
结论:
- 多个PIK3CA突变代表一个显著的致癌事件.
- 双重PIK3CA突变的存在增加了瘤信号和瘤生长.
- 患有双重PIK3CA突变的患者对PI3Kα抑制剂的敏感性增加,这表明潜在的治疗分层.
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