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

被引：215

作者：

Vasan, Neil ^{[1
,2
,3
]}

Razavi, Pedram ^{[1
,2
]}

Johnson, Jared L. ^{[3
]}

Shao, Hong ^{[1
]}

Shah, Hardik ^{[4
]}

Antoine, Alesia ^{[4
]}

Ladewig, Erik ^{[1
]}

Gorelick, Alexander ^{[1
,5
]}

Lin, Ting-Yu ^{[3
]}

Toska, Eneda ^{[1
]}

Xu, Guotai ^{[1
]}

Kazmi, Abiha ^{[1
]}

Chang, Matthew T. ^{[6
]}

Taylor, Barry S. ^{[1
,5
,7
]}

Dickler, Maura N. ^{[2
,8
]}

Jhaveri, Komal ^{[2
]}

Chandarlapaty, Sarat ^{[1
,2
]}

Rabadan, Raul ^{[9
,10
]}

Reznik, Ed ^{[5
,7
]}

Smith, Melissa L. ^{[4
,11
]}

Sebra, Robert ^{[4
,11
,12
]}

Schimmoller, Frauke ^{[6
]}

Wilson, Timothy R. ^{[6
]}

Friedman, Lori S. ^{[13
]}

Cantley, Lewis C. ^{[3
]}

Scaltriti, Maurizio ^{[1
,14
]}

Baselga, Jose ^{[1
,2
,15
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave, New York, NY 10021 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[3] Weill Cornell Med Coll, Dept Med, Meyer Canc Ctr, New York, NY USA

[4] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[5] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[6] Genentech Inc, San Francisco, CA USA

[7] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, 1275 York Ave, New York, NY 10021 USA

[8] Eli Lilly & Co, Indianapolis, IN 46285 USA

[9] Columbia Univ, Dept Syst Biol, New York, NY USA

[10] Columbia Univ, Dept Biomed Informat, New York, NY USA

[11] Icahn Sch Med Mt Sinai, Icahn Inst Data Sci & Genom Technol, New York, NY 10029 USA

[12] Sema4, Stamford, CT USA

[13] ORIC Pharmaceut, San Francisco, CA USA

[14] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[15] AstraZeneca, Gaithersburg, MD USA

来源：

SCIENCE | 2019年 / 366卷 / 6466期

基金：

美国国家科学基金会;

关键词：

ABL TYROSINE KINASE; BREAST-CANCER; CATALYTIC SUBUNIT; LIPID-BINDING; PI3K PATHWAY; PTEN LOSS; P110-ALPHA; LANDSCAPE; GROWTH; ACTIVATION;

D O I：

10.1126/science.aaw9032

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Activating mutations in PIK3CA are frequent in human breast cancer, and phosphoinositide 3-kinase alpha (Pl3K alpha) 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 P13K activity, enhanced downstream signaling, increased cell proliferation, and tumor growth. The biochemical mechanisms of dual mutations include increased disruption of p110 alpha binding to the inhibitory subunit p85 alpha, which relieves its catalytic inhibition, and increased p110 alpha membrane lipid binding. Double PIK3CA mutations predict increased sensitivity to PI3K alpha inhibitors compared with single-hotspot mutations.

引用

页码：714 / +

页数：78

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