Inhibitors that activate

• Published in: Nature (London) Vol. 464; no. 7287; pp. 358 - 359
• Main Authors: Cichowski, Karen, Jänne, Pasi A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.03.2010; Nature Publishing Group
• Subjects: 631/154; 631/67/1059/602; 692/699/67/1813/1634; Antimitotic agents; Antineoplastic agents; Cancer; Cancer therapies; Complications and side effects; Crystal structure; Dosage and administration; Drug therapy; Enzyme inhibitors; Humanities and Social Sciences; Inhibitors; Melanoma; multidisciplinary; Mutants; Mutation; news-and-views; Science; Science (multidisciplinary); Studies; Tissues; Tumors; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/464358a

Inhibitors of RAF enzymes can suppress or activate the same signalling pathway. The details of how this happens provide a cautionary note for those targeting the pathway for anticancer drug discovery. Mixed signals from RAF Abnormal activation of the RAS-RAF-MEK-ERK signalling pathway is a feature of many human cancers, making it an attractive target for antitumour therapy. Several RAF and MEK inhibitors are in clinical trials, but an unexpected complication has emerged. Although selective BRAF inhibitors are effective in treating mutant BRAF melanoma, in which they potently suppress RAF-MEK-ERK signalling, the same inhibitors are ineffective against tumours that carry an oncogenic mutation in the KRAS gene. Two groups now report that the reason for this dramatic difference is that RAF 'inhibitors' have dual activity, functioning as either inhibitors or activators of RAF, depending on the cellular context and mutational status of RAF . In News & Views, Karen Cichowski and Pasi Jänne discuss the mechanistic and clinical implications of these findings and similar work reported in Cell .