Interactions between PTEN and receptor tyrosine kinase pathways and their implications for glioma therapy.
Gliomas are the most common and deadly form of malignant primary brain tumors. Loss of the tumor-suppressor PTEN and activation of the receptor tyrosine kinases (RTKs) EGF receptor, c-Met, PDGF receptor and VEGF receptor are among the most common molecular dysfunctions associated with glioma malignancy. PTEN interacts with RTK-dependent signaling at multiple levels. These include the ability of PTEN to counteract PI3K activation by RTKs, as well as possible effects of PTEN on RTK activation of the MAPK pathway and RTK-dependent gene-expression regulation. Consequently, PTEN expression affects RTK-induced malignancy. Importantly, the PTEN status was recently found to be critical for the outcome of RTK-targeted clinical therapies that have been developed recently. Combining RTK-targeted therapies with therapies aimed at counteracting the effects of PTEN loss, such as mTOR inhibition, might also have therapeutic advantage. This article reviews the known molecular and functional interactions between PTEN and RTK pathways and their implications for glioma therapy.
Abounader
Roger
R
Departments of Neurology and Microbiology, University of Virginia Health System, Charlottesville, VA 22908, USA. ra6u@virginia.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D020794:Receptor Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human