Ras/Raf signalling and emerging pharmacotherapeutic targets.
The Ras-Raf-MEK-ERK pathway is a ubiquitously expressed signalling module that regulates the proliferation, differentiation and survival of cells. This pathway features several oncogenes and is deregulated in approximately 30% of all human cancers. Thus, it has emerged as a prime target for antitumour therapy. Drugs targeting Ras, Raf or MEK are currently in clinical trials. They comprise vaccines, isoprenylation inhibitors, antisense compounds and kinase inhibitors. Most are remarkably well tolerated and some show promising efficacy. However, it is not clear which components of this pathway should be targeted and how maximum efficacy can be achieved. This paper reviews the current efforts with an emphasis on new mechanistic and conceptual approaches.
Kolch
Walter
W
The Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Glasgow, UK. wkolch@beatson.gla.ac.uk
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000494:pharmacology / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use; D017368:Protein Prenylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D004791:Enzyme Inhibitors; D016376:Oligonucleotides, Antisense; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D018631:ras Proteins