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

Krishna M. Vasudevan, David A. Barbie, Michael A. Davies, Rosalia Rabinovsky, Chontelle J. McNear, Jessica J. Kim, Bryan T. Hennessy, Hsiuyi Tseng, Panisa Pochanard, So Young Kim, Ian F. Dunn, Anna C. Schinzel, Peter Sandy, Sebastian Hoersch, Qing Sheng, Piyush B. Gupta, Jesse S. Boehm, Jan H. Reiling, Serena Silver, Yiling Lu & 14 others Katherine Stemke-Hale, Bhaskar Dutta, Corwin Joy, Aysegul A. Sahin, Ana Maria Gonzalez-Angulo, Ana Lluch, Lucia E. Rameh, Tyler Jacks, David E. Root, Eric S. Lander, Gordon Mills, William C. Hahn, William R. Sellers, Levi A. Garraway

Research output: Contribution to journalArticle

361 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)21-32
Number of pages12
JournalCancer Cell
Volume16
Issue number1
DOIs
StatePublished - Jul 7 2009
Externally publishedYes

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Phosphatidylinositol 3-Kinase
Mutation
Neoplasms
Phosphoproteins
Oncogenes
Carcinogenesis
Phosphotransferases
Breast Neoplasms
Cell Line
Membranes
Growth

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Vasudevan, K. M., Barbie, D. A., Davies, M. A., Rabinovsky, R., McNear, C. J., Kim, J. J., ... Garraway, L. A. (2009). AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer. Cancer Cell, 16(1), 21-32. https://doi.org/10.1016/j.ccr.2009.04.012

AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer. / Vasudevan, Krishna M.; Barbie, David A.; Davies, Michael A.; Rabinovsky, Rosalia; McNear, Chontelle J.; Kim, Jessica J.; Hennessy, Bryan T.; Tseng, Hsiuyi; Pochanard, Panisa; Kim, So Young; Dunn, Ian F.; Schinzel, Anna C.; Sandy, Peter; Hoersch, Sebastian; Sheng, Qing; Gupta, Piyush B.; Boehm, Jesse S.; Reiling, Jan H.; Silver, Serena; Lu, Yiling; Stemke-Hale, Katherine; Dutta, Bhaskar; Joy, Corwin; Sahin, Aysegul A.; Gonzalez-Angulo, Ana Maria; Lluch, Ana; Rameh, Lucia E.; Jacks, Tyler; Root, David E.; Lander, Eric S.; Mills, Gordon; Hahn, William C.; Sellers, William R.; Garraway, Levi A.

In: Cancer Cell, Vol. 16, No. 1, 07.07.2009, p. 21-32.

Research output: Contribution to journalArticle

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, G, Hahn, WC, Sellers, WR & Garraway, LA 2009, 'AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer', Cancer Cell, vol. 16, no. 1, pp. 21-32. https://doi.org/10.1016/j.ccr.2009.04.012
Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ et al. AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer. Cancer Cell. 2009 Jul 7;16(1):21-32. https://doi.org/10.1016/j.ccr.2009.04.012
Vasudevan, Krishna M. ; Barbie, David A. ; Davies, Michael A. ; Rabinovsky, Rosalia ; McNear, Chontelle J. ; Kim, Jessica J. ; Hennessy, Bryan T. ; Tseng, Hsiuyi ; Pochanard, Panisa ; Kim, So Young ; Dunn, Ian F. ; Schinzel, Anna C. ; Sandy, Peter ; Hoersch, Sebastian ; Sheng, Qing ; Gupta, Piyush B. ; Boehm, Jesse S. ; Reiling, Jan H. ; Silver, Serena ; Lu, Yiling ; Stemke-Hale, Katherine ; Dutta, Bhaskar ; Joy, Corwin ; Sahin, Aysegul A. ; Gonzalez-Angulo, Ana Maria ; Lluch, Ana ; Rameh, Lucia E. ; Jacks, Tyler ; Root, David E. ; Lander, Eric S. ; Mills, Gordon ; Hahn, William C. ; Sellers, William R. ; Garraway, Levi A. / AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer. In: Cancer Cell. 2009 ; Vol. 16, No. 1. pp. 21-32.
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