TY - JOUR
T1 - Activation of AKT kinases in cancer
T2 - Implications for therapeutic targeting
AU - Bellacosa, Alfonso
AU - Kumar, C. Chandra
AU - Cristofano, Antonio Di
AU - Testa, Joseph Robert
N1 - Funding Information:
The authors thank Drs. Vince Madison, William Windsor, and Philip Tsichlis for helpful discussions and critical review of the manuscript, Dr. Xiao Li for providing figures of homology models of AKT family members, Drs. Andres Klein‐Szanto and Binaifer Balsara for preparing immunohistochemistry figures, and Kathryn Ireton and Rose Sonlin for secretarial assistance. This work was supported by NIH Grants CA105008, CA77429, CA83638 (SPORE in Ovarian Cancer), CA105008, CA097097, and CA06927 and by an appropriation from the Commonwealth of Pennsylvania to the Fox Chase Cancer Center.
PY - 2005
Y1 - 2005
N2 - 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.
AB - 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.
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U2 - 10.1016/S0065-230X(05)94002-5
DO - 10.1016/S0065-230X(05)94002-5
M3 - Review article
C2 - 16095999
AN - SCOPUS:23944526062
SN - 0065-230X
VL - 94
SP - 29
EP - 86
JO - Advances in Cancer Research
JF - Advances in Cancer Research
IS - 1 SUPPL.
ER -