PIK3CA是磷脂醯肌醇-3-羥激酶（PI3K）催化亞基p110α蛋白的編碼基因，可以通過下遊PI3K→蛋白激酶B（AKT）信號轉化傳導通路，對正常細胞的生存、生長和繁殖發揮重要作用。PIK3CA突變可以引起PI3K→AKT異常激活，引起腫瘤細胞的生存、生長和繁殖。人類乳腺癌等多種腫瘤組織可以發現PIK3CA突變，故阿培利司（阿吡利塞）等PI3Kα抑制劑已被批准用於治療。不過，PI3Kα抑制劑對於PIK3CA突變患者的療效懸殊，此類藥物敏感性的決定因素尚不明確。
2019年11月8日，全球自然科學三大旗艦期刊之一、美國科學促進會《科學》正刊發表紐約紀念醫院斯隆凱特林癌症中心、康奈爾大學威爾醫學院、西奈山伊坎醫學院、基因泰克、禮來、哥倫比亞大學、SEMA4、ORIC的研究報告，對PIK3CA突變癌基因組進行分析，結果出乎意料地發現，部分乳腺癌的PIK3CA並非單突變，而是雙突變，並且發生於同一染色體的等位基因，既可促進腫瘤的發生和發展，也可增強PI3Kα抑制劑的敏感性。
該研究觀察到12%～15%的乳腺癌以及其他類型腫瘤PIK3CA存在多種突變，其中絕大多數（95%）為雙突變。PIK3CA雙突變位於同一對染色體的等位基因，可以引起PI3K活性增加、下遊信號轉化傳導增強、細胞繁殖和腫瘤生長加快。雙突變的生物化學機制，包括催化亞基p110α與抑制亞基p85α的結合被不斷破壞，從而減輕其催化抑制作用，並且增加p110α與細胞膜脂質的結合。
此外，對於臨床研究數據的初步分析表明，PIK3CA雙突變與單突變的乳腺癌相比，對PI3K抑制劑更敏感，可以預測PI3Kα抑制劑的敏感性增強。
因此，該研究結果表明，PIK3CA突變狀態可以幫助確定最有可能對PI3Kα抑制劑獲益的乳腺癌患者。
對此，哈佛大學醫學院、貝斯以色列和新英格蘭女執事醫療中心病理學教授亞歷克斯·託克發表同期報導：癌基因的雙重麻煩。
Science. 2019 Nov 8;366(6466):714-723.
Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.
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.
Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA; Genentech, South San Francisco, CA, USA; Eli Lilly and Company, Indianapolis, IN, USA; Columbia University, New York, NY, USA; Sema4, Stamford, CT, USA; ORIC Pharmaceuticals, South San Francisco, CA, USA.
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.
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.
DOI: 10.1126/science.aaw9032
Science. 2019 Nov 8;366(6466):685-686.
Double trouble for cancer gene.
Alex Toker.
Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA.
DOI: 10.1126/science.aaz4016