AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Vasudevan, KM; Barbie, DA; Davies, MA; Rabinovsky, R; McNear, CJ; Kim, JJ; Hennessy, BT; Tseng, H; Pochanard, P; Kim, SY; Dunn, IF; Schinzel, AC; Sandy, P; Hoersch, S; Sheng, Q; Gupta, PB; Boehm, JS; Reiling, JH; Silver, S; Lu, Y; Stemke-Hale, K; Dutta, B; Joy, C; Sahin, AA; Gonzalez-Angulo, AM; Lluch, A; Rameh, LE; Jacks, T; Root, DE; Lander, ES; Mills, GB; Hahn, WC; Sellers, WR; Garraway, LA

Published Date

  • July 7, 2009

Published In

Volume / Issue

  • 16 / 1

Start / End Page

  • 21 - 32

PubMed ID

  • 19573809

Pubmed Central ID

  • 19573809

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2009.04.012

Language

  • eng

Conference Location

  • United States