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

共 56 条

[1] Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha [J].

Alessi, DR ;

James, SR ;

Downes, CP ;

Holmes, AB ;

Gaffney, PRJ ;

Reese, CB ;

Cohen, P .

CURRENT BIOLOGY, 1997, 7 (04) :261-269

[2] Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas [J].

Barbareschi, Mattia ;

Buttitta, Fiamma ;

Felicioni, Lara ;

Cotrupi, Sabrina ;

Barassi, Fabio ;

Del Grammastro, Maela ;

Ferro, Antonella ;

Palma, Paolo Dalla ;

Galligioni, Enzo ;

Marchetti, Antonio .

CLINICAL CANCER RESEARCH, 2007, 13 (20) :6064-6069

[3] Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN+/- mice [J].

Bayascas, JR ;

Leslie, NR ;

Parsons, R ;

Fleming, S ;

Alessi, DR .

CURRENT BIOLOGY, 2005, 15 (20) :1839-1846

[4] Labeling anti-HER2/neu monoclonal antibodies with 111In and 90Y using a bifunctional DTPA chelating agent [J].

Blend, MJ ;

Stastny, JJ ;

Swanson, SM ;

Brechbiel, MW .

CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS, 2003, 18 (03) :355-363

[5] Integrative genomic approaches identify IKBKE as a breast cancer oncogene [J].

Boehm, Jesse S. ;

Zhao, Jean J. ;

Yao, Jun ;

Kim, So Young ;

Firestein, Ron ;

Dunn, Ian F. ;

Sjostrom, Sarah K. ;

Garraway, Levi A. ;

Weremowicz, Stanislawa ;

Richardson, Andrea L. ;

Greulich, Heidi ;

Stewart, Carly J. ;

Mulvey, Laura A. ;

Shen, Rhine R. ;

Ambrogio, Lauren ;

Hirozane-Kishikawa, Tomoko ;

Hill, David E. ;

Vidal, Marc ;

Meyerson, Matthew ;

Grenier, Jennifer K. ;

Hinkle, Greg ;

Root, David E. ;

Roberts, Thomas M. ;

Lander, Eric S. ;

Polyak, Kornelia ;

Hahn, William C. .

CELL, 2007, 129 (06) :1065-1079

[6] Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor [J].

Brunet, A ;

Bonni, A ;

Zigmond, MJ ;

Lin, MZ ;

Juo, P ;

Hu, LS ;

Anderson, MJ ;

Arden, KC ;

Blenis, J ;

Greenberg, ME .

CELL, 1999, 96 (06) :857-868

[7] A transforming mutation in the pleckstrin homology domain of AKT1 in cancer [J].

Carpten, John D. ;

Faber, Andrew L. ;

Horn, Candice ;

Donoho, Gregory P. ;

Briggs, Stephen L. ;

Robbins, Christiane M. ;

Hostetter, Galen ;

Boguslawski, Sophie ;

Moses, Tracy Y. ;

Savage, Stephanie ;

Uhlik, Mark ;

Lin, Aimin ;

Du, Jian ;

Qian, Yue-Wei ;

Zeckner, Douglas J. ;

Tucker-Kellogg, Greg ;

Touchman, Jeffrey ;

Patel, Ketan ;

Mousses, Spyro ;

Bittner, Michael ;

Schevitz, Richard ;

Lai, Mei-Huei T. ;

Blanchard, Kerry L. ;

Thomas, James E. .

NATURE, 2007, 448 (7152) :439-U1

[8] Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1:: identification of five sites of phosphorylation in vivo [J].

Casamayor, A ;

Morrice, NA ;

Alessi, DR .

BIOCHEMICAL JOURNAL, 1999, 342 :287-292

[9] Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1 [J].

Currie, RA ;

Walker, KS ;

Gray, A ;

Deak, M ;

Casamayor, A ;

Downes, CP ;

Cohen, P ;

Alessi, DR ;

Lucocq, J .

BIOCHEMICAL JOURNAL, 1999, 337 :575-583

[10] Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer [J].

Depowski, PL ;

Rosenthal, SI ;

Ross, JS .

MODERN PATHOLOGY, 2001, 14 (07) :672-676

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