Activation of AKT kinases in cancer: Implications for therapeutic targeting

Alfonso Bellacosa, C. Chandra Kumar, Antonio Di Cristofano, Joseph Robert Testa

Research output: Contribution to journalArticle

583 Citations (Scopus)

Abstract

The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase. An ever-increasing list of AKT substrates has precisely defined the multiple functions of this kinase family in normal physiology and disease states. Cellular processes regulated by AKT include cell proliferation and survival, cell size and response to nutrient availability, intermediary metabolism, angiogenesis, and tissue invasion. All these processes represent hallmarks of cancer, and a burgeoning literature has defined the importance of AKT alterations in human cancer and experimental models of tumorigenesis, continuing the legacy represented by the original identification of v-Akt as the transforming oncogene of a murine retrovirus. Many oncoproteins and tumor suppressors intersect in the AKT pathway, finely regulating cellular functions at the interface of signal transduction and classical metabolic regulation. This careful balance is altered in human cancer by a variety of activating and inactivating mechanisms that target both AKT and interrelated proteins. Reprogramming of this altered circuitry by pharmacologic modulation of the AKT pathway represents a powerful strategy for rational cancer therapy. In this review, we summarize a large body of data, from many types of cancer, indicating that AKT activation is one of the most common molecular alterations in human malignancy. We also review mechanisms of activation of AKT kinases, examples of therapeutic modulation of the AKT pathway in animal models, and the current status of efforts to target molecular components of the AKT pathway for cancer therapy and, possibly, cancer prevention.

Original languageEnglish (US)
Pages (from-to)29-86
Number of pages58
JournalAdvances in Cancer Research
Volume94
Issue number1 SUPPL.
DOIs
StatePublished - 2005
Externally publishedYes

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Phosphotransferases
Neoplasms
Therapeutics
Signal Transduction
Phosphatidylinositol 3-Kinase
Oncogene Proteins
Retroviridae
Cell Size
Oncogenes
Protein-Tyrosine Kinases
Cell Survival
Carcinogenesis
Theoretical Models
Animal Models
Cell Proliferation
Food
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Activation of AKT kinases in cancer : Implications for therapeutic targeting. / Bellacosa, Alfonso; Kumar, C. Chandra; Di Cristofano, Antonio; Testa, Joseph Robert.

In: Advances in Cancer Research, Vol. 94, No. 1 SUPPL., 2005, p. 29-86.

Research output: Contribution to journalArticle

Bellacosa, Alfonso ; Kumar, C. Chandra ; Di Cristofano, Antonio ; Testa, Joseph Robert. / Activation of AKT kinases in cancer : Implications for therapeutic targeting. In: Advances in Cancer Research. 2005 ; Vol. 94, No. 1 SUPPL. pp. 29-86.
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