美国纪念斯隆-凯特琳癌症中心José Baselga 和Maurizio Scaltriti等研究人员合作发现，PIK3CA基因双拷贝突变顺式增加致瘤性和对PI3Kα抑制剂的敏感性。这一研究成果2019年11月7日发表在国际学术期刊《科学》上。

研究人员表示，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敏感性的决定因素，研究人员分析了PIK3CA突变的癌症基因组，并观察到12-15％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％）是双拷贝突变。PIK3CA双拷贝突变在同一等位基因上顺式排列，并导致PI3K活性增加，下游信号传导增强，细胞增殖和肿瘤生长。双拷贝突变的生化机制包括增加p110α与抑制性亚基p85α结合的破坏，从而减轻其催化抑制作用，并增强p110α膜脂质结合。与单热点突变相比，PIK3CA双突变能够预测对PI3Kα抑制剂敏感性的增加。

附：英文原文

Title: Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors

Author: Neil Vasan, Pedram Razavi, Jared L. Johnson, Hong Shao, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T. Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L. Smith, Robert Sebra, Frauke Schimmoller, Timothy R. Wilson, Lori S. Friedman, Lewis C. Cantley, Maurizio Scaltriti, José Baselga

Issue&Volume: Volume 366 Issue 6466

Abstract: 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.

DOI: 10.1126/science.aaw9032

Source:https://science.sciencemag.org/content/366/6466/714