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.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors: Krishna M
authors: KM
authors: Vasudevan
authors: David A
authors: DA
authors: Barbie
authors: Michael A
authors: MA
authors: Davies
authors: Rosalia
authors: R
authors: Rabinovsky
authors: Chontelle J
authors: CJ
authors: McNear
authors: Jessica J
authors: JJ
authors: Kim
authors: Bryan T
authors: BT
authors: Hennessy
authors: Hsiuyi
authors: H
authors: Tseng
authors: Panisa
authors: P
authors: Pochanard
authors: So Young
authors: SY
authors: Kim
authors: Ian F
authors: IF
authors: Dunn
authors: Anna C
authors: AC
authors: Schinzel
authors: Peter
authors: P
authors: Sandy
authors: Sebastian
authors: S
authors: Hoersch
authors: Qing
authors: Q
authors: Sheng
authors: Piyush B
authors: PB
authors: Gupta
authors: Jesse S
authors: JS
authors: Boehm
authors: Jan H
authors: JH
authors: Reiling
authors: Serena
authors: S
authors: Silver
authors: Yiling
authors: Y
authors: Lu
authors: Katherine
authors: K
authors: Stemke-Hale
authors: Bhaskar
authors: B
authors: Dutta
authors: Corwin
authors: C
authors: Joy
authors: Aysegul A
authors: AA
authors: Sahin
authors: Ana Maria
authors: AM
authors: Gonzalez-Angulo
authors: Ana
authors: A
authors: Lluch
authors: Lucia E
authors: LE
authors: Rameh
authors: Tyler
authors: T
authors: Jacks
authors: David E
authors: DE
authors: Root
authors: Eric S
authors: ES
authors: Lander
authors: Gordon B
authors: GB
authors: Mills
authors: William C
authors: WC
authors: Hahn
authors: William R
authors: WR
authors: Sellers
authors: Levi A
authors: LA
authors: Garraway
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000235:genetics; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000631429:PDK1 protein, human; C484760:PIK3CA protein, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases; C494929:PTEN protein, human