Seeing double can be a good thing Many human breast cancers harbor activating mutations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide 3-kinase (PI3K). Clinical trials are underway to evaluate the efficacy of PI3K inhibitors in cancer patients. Vasan et al. found unexpectedly that a subset of breast cancers harbor not one—but two—PIK3CA mutations, and the mutations occur on the same allele (see the Perspective by Toker). In model systems, the double mutations hyperactivate PI3K signaling and enhance tumor growth. Preliminary analysis of clinical trial data suggests that breast cancers with double mutations are more responsive to PI3K inhibitors than those with a single mutation. PIK3CA mutational status could help identify the breast cancer patients most likely to benefit from these drugs. Science, this issue p. 714; see also p. 685 Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (PI3Kα) inhibitors have been approved for therapy. To characterize determinants of sensitivity to these agents, we analyzed PIK3CA-mutant cancer genomes and observed the presence of multiple PIK3CA mutations in 12 to 15% of breast cancers and other tumor types, most of which (95%) are double mutations. Double PIK3CA mutations are in cis on the same allele and result in increased PI3K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased p110α membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3Kα inhibitors compared with single-hotspot mutations. Some breast cancers harbor not one—but two—PIK3CA mutations, and this enhances their response to certain drugs.

中文翻译：

---

顺式双 PIK3CA 突变增加致癌性和对 PI3Kα 抑制剂的敏感性

看到双重可能是一件好事 许多人类乳腺癌在 PIK3CA 中存在激活突变，PIK3CA 是编码磷酸肌醇 3-激酶 (PI3K) 催化亚基的基因。正在进行临床试验以评估 PI3K 抑制剂对癌症患者的疗效。瓦桑等人。出人意料地发现，一部分乳腺癌携带的不是一个而是两个 PIK3CA 突变，并且这些突变发生在同一个等位基因上（参见 Toker 的观点）。在模型系统中，双突变过度激活 PI3K 信号并促进肿瘤生长。对临床试验数据的初步分析表明，双突变的乳腺癌比单突变的乳腺癌对 PI3K 抑制剂更敏感。PIK3CA 突变状态可以帮助确定最有可能从这些药物中受益的乳腺癌患者。科学，这个问题 p。714; 另见第。685 PIK3CA 中的激活突变在人类乳腺癌中很常见，磷酸肌醇 3-激酶 α (PI3Kα) 抑制剂已被批准用于治疗。为了表征对这些药物的敏感性的决定因素，我们分析了 PIK3CA 突变的癌症基因组，并观察到 ​​12% 至 15% 的乳腺癌和其他肿瘤类型中存在多个 PIK3CA 突变，其中大多数 (95%) 是双突变。双 PIK3CA 突变在同一等位基因上呈顺式排列，导致 PI3K 活性增加、下游信号传导增强、细胞增殖增加和肿瘤生长。双突变的生化机制包括增加对 p110α 与抑制性亚基 p85α 结合的破坏，从而减轻其催化抑制，并增加 p110α 膜脂结合。与单热点突变相比，双 PIK3CA 突变预测对 PI3Kα 抑制剂的敏感性增加。一些乳腺癌携带的不是一个而是两个 PIK3CA 突变，这增强了它们对某些药物的反应。