PI3K pathway alterations in cancer: variations on a theme

• Published in: Oncogene Vol. 27; no. 41; pp. 5497 - 5510
• Main Authors: Yuan, T L, Cantley, L C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.09.2008; Nature Publishing; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis; Biological and medical sciences; Cancer; Care and treatment; Cell Biology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Clinical trials; Dosage and administration; Enzyme inhibitors; Enzyme Inhibitors - therapeutic use; Fundamental and applied biological sciences. Psychology; Genes, erbB-2 - physiology; Genes, ras - physiology; Genetic aspects; Genetics; Health aspects; Human Genetics; Humans; Inhibitor drugs; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Methods; Models, Biological; Molecular and cellular biology; Mutation - physiology; Neoplasms - drug therapy; Neoplasms - genetics; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Oncology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - physiology; Protein kinases; PTEN Phosphohydrolase - antagonists & inhibitors; PTEN Phosphohydrolase - genetics; PTEN protein; review; Signal Transduction - genetics; Signal Transduction - physiology; Solid tumors; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - physiology; Tumors; Tyrosine; United States; PTEN; tumorigenesis; PI3K; HER2; C-Onc gene; Malignant tumor; Carcinogenesis; Cancer; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.245

The high frequency of phosphoinositide 3-kinase (PI3K) pathway alterations in cancer has led to a surge in the development of PI3K inhibitors. Many of these targeted therapies are currently in clinical trials and show great promise for the treatment of PI3K-addicted tumors. These recent developments call for a re-evaluation of the oncogenic mechanisms behind PI3K pathway alterations. This pathway is unique in that every major node is frequently mutated or amplified in a wide variety of solid tumors. Receptor tyrosine kinases upstream of PI3K, the p110α catalytic subunit of PI3K, the downstream kinase, AKT, and the negative regulator, PTEN, are all frequently altered in cancer. In this review, we will examine the oncogenic properties of these genetic alterations to understand whether they are redundant or distinct and propose treatment strategies tailored for these genetic lesions.