PI3 kinases in cancer: from oncogene artifact to leading cancer target.
At the time of its discovery in the 1980s, the lipid kinase activity found associated with certain viral oncoproteins, which we now know to originate from the class IA phosphatidylinositide 3-kinases (PI3Ks), was thought by many to be a purification artifact. Subsequent work identified these enzymes as key regulators of cell signaling pathways that control various cellular processes including proliferation, motility, survival, and apoptosis. It is now clear that the PI3K pathway is activated by genetic or epigenetic alterations in a large proportion of human tumors, and a search for small molecule inhibitors of PI3K activity is currently a major effort of the pharmaceutical industry. However, because of the importance of PI3Ks in normal physiology, the road to therapeutics might not be smooth and could require further dissection of PI3K signaling pathways. In particular, it may be important to distinguish among the roles of the various isoforms of class 1A PI3K in both normal physiology and tumorigenesis.
Zhao
Jean J
JJ
Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Harvard Medical School, Boston, MA 02115, USA.
Roberts
Thomas M
TM
D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018631:ras Proteins; C446603:TPTE protein, human