@article{a07d8381295f49bea1f0cde93765ba47,
title = "AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer",
abstract = "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.",
keywords = "CELLCYCLE",
author = "Vasudevan, {Krishna M.} and Barbie, {David A.} and Davies, {Michael A.} and Rosalia Rabinovsky and McNear, {Chontelle J.} and Kim, {Jessica J.} and Hennessy, {Bryan T.} and Hsiuyi Tseng and Panisa Pochanard and Kim, {So Young} and Dunn, {Ian F.} and Schinzel, {Anna C.} and Peter Sandy and Sebastian Hoersch and Qing Sheng and Gupta, {Piyush B.} and Boehm, {Jesse S.} and Reiling, {Jan H.} and Serena Silver and Yiling Lu and Katherine Stemke-Hale and Bhaskar Dutta and Corwin Joy and Sahin, {Aysegul A.} and Gonzalez-Angulo, {Ana Maria} and Ana Lluch and Rameh, {Lucia E.} and Tyler Jacks and Root, {David E.} and Lander, {Eric S.} and Mills, {Gordon B.} and Hahn, {William C.} and Sellers, {William R.} and Garraway, {Levi A.}",
note = "Funding Information: We thank Erica Bauerlein for shRNA constructs; Len Pennacchio, Jan-Fang Cheng, Mandy Madiredio, Stefan Frohling, Claudia Scholl, and Raymond Wadlow for technical assistance; Tamas Balla for the PH-AKT GFP construct; Pablo Tamayo for statistical help; and Payman Amiri, Stephen Basham, Amit Dutt, Matthew Meyerson, David Livingston, David Sabatini, and members of the Garraway laboratory for helpful discussions. This work was supported by the Prostate Cancer Foundation, the Burroughs-Wellcome Fund (L.A.G.), the Department of Defense grant PC073284 (K.M.V.), the American Society for Clinical Oncology (M.A.D.); the Human Frontier Fellowship Organization (J.H.R.); the National Human Genome Research Institute (E.S.L.); the Susan Madden Fund (D.A.B.); the Starr Cancer Consortium 1A-11 (W.C.H.); and the National Institutes of Health grants T32CA09172-33 (D.A.B.), P50CA093459 (M.A.D.), R33CA128625, P01CA050661 (W.C.H.), P50CA112967, P30CA14051 (T.J.), R01CA085912 (W.R.S. and L.A.G.), and DP2OD002750-01 (L.A.G.). G.B.M. is a consultant for Amira Pharmaceuticals, Inc., Arcxis Biotechnologies, Catena Pharmaceuticals, Genentech, Inc., GlaxoSmithKline, Lpath Therapeutics, PTV Sciences, QLT, Inc., Semafore Pharmaceuticals, and Signal Pharmaceuticals. W.R.S. is an employee for Novartis, Inc. W.C.H. and L.A.G. are consultants for and received sponsored research support from Novartis, Inc. ",
year = "2009",
month = jul,
day = "7",
doi = "10.1016/j.ccr.2009.04.012",
language = "English (US)",
volume = "16",
pages = "21--32",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",
}