AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer

被引：467

作者：

Vasudevan, Krishna M. ^{[1
,2
,3
]}

Barbie, David A. ^{[1
,5
,12
]}

Davies, Michael A. ^{[7
]}

Rabinovsky, Rosalia ^{[1
,2
,3
]}

McNear, Chontelle J. ^{[1
,2
]}

Kim, Jessica J. ^{[1
,2
]}

Hennessy, Bryan T. ^{[7
]}

Tseng, Hsiuyi ^{[1
]}

Pochanard, Panisa ^{[1
]}

Kim, So Young ^{[1
,2
,5
]}

Dunn, Ian F. ^{[1
,2
,3
,4
,5
]}

Schinzel, Anna C. ^{[1
,2
,5
]}

Sandy, Peter ^{[8
]}

Hoersch, Sebastian ^{[8
]}

Sheng, Qing ^{[1
,3
,4
]}

Gupta, Piyush B. ^{[5
]}

Boehm, Jesse S. ^{[5
]}

Reiling, Jan H. ^{[9
]}

Silver, Serena ^{[5
]}

Lu, Yiling ^{[7
]}

Stemke-Hale, Katherine ^{[7
]}

Dutta, Bhaskar ^{[7
]}

Joy, Corwin ^{[7
]}

Sahin, Aysegul A. ^{[7
]}

Gonzalez-Angulo, Ana Maria ^{[7
]}

Lluch, Ana ^{[10
]}

Rameh, Lucia E. ^{[11
]}

Jacks, Tyler ^{[8
]}

Root, David E. ^{[5
]}

Lander, Eric S. ^{[5
]}

Mills, Gordon B. ^{[7
]}

Hahn, William C. ^{[1
,2
,3
,4
,5
]}

Sellers, William R. ^{[1
,6
]}

Garraway, Levi A. ^{[1
,2
,3
,5
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA

[5] Broad Inst MIT & Harvard, Cambridge Ctr 7, Cambridge, MA 02142 USA

[6] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[8] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[9] Whitehead Inst Biomed Res, Cambridge Ctr 9, Cambridge, MA 02142 USA

[10] Univ Valencia, Clin Hosp, Valencia 46010, Spain

[11] Boston Biomed Res Inst, Watertown, MA 02472 USA

[12] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

来源：

CANCER CELL | 2009年 / 16卷 / 01期

基金：

美国国家卫生研究院;

关键词：

3-PHOSPHOINOSITIDE-DEPENDENT PROTEIN KINASE-1; MAMMARY EPITHELIAL-CELLS; HYDROPHOBIC MOTIF PHOSPHORYLATION; BREAST-CANCER; PHOSPHATIDYLINOSITOL; 3-KINASES; CAENORHABDITIS-ELEGANS; HOMOLOGY DOMAIN; HIGH-FREQUENCY; MTOR COMPLEX; ACTIVATION;

D O I：

10.1016/j.ccr.2009.04.012

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.

引用

页码：21 / 32

页数：12

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