Publication Date:
2010-02-05
Description:
Activating mutations in KRAS and BRAF are found in more than 30% of all human tumours and 40% of melanoma, respectively, thus targeting this pathway could have broad therapeutic effects. Small molecule ATP-competitive RAF kinase inhibitors have potent antitumour effects on mutant BRAF(V600E) tumours but, in contrast to mitogen-activated protein kinase kinase (MEK) inhibitors, are not potent against RAS mutant tumour models, despite RAF functioning as a key effector downstream of RAS and upstream of MEK. Here we show that ATP-competitive RAF inhibitors have two opposing mechanisms of action depending on the cellular context. In BRAF(V600E) tumours, RAF inhibitors effectively block the mitogen-activated protein kinase (MAPK) signalling pathway and decrease tumour growth. Notably, in KRAS mutant and RAS/RAF wild-type tumours, RAF inhibitors activate the RAF-MEK-ERK pathway in a RAS-dependent manner, thus enhancing tumour growth in some xenograft models. Inhibitor binding activates wild-type RAF isoforms by inducing dimerization, membrane localization and interaction with RAS-GTP. These events occur independently of kinase inhibition and are, instead, linked to direct conformational effects of inhibitors on the RAF kinase domain. On the basis of these findings, we demonstrate that ATP-competitive kinase inhibitors can have opposing functions as inhibitors or activators of signalling pathways, depending on the cellular context. Furthermore, this work provides new insights into the therapeutic use of ATP-competitive RAF inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hatzivassiliou, Georgia -- Song, Kyung -- Yen, Ivana -- Brandhuber, Barbara J -- Anderson, Daniel J -- Alvarado, Ryan -- Ludlam, Mary J C -- Stokoe, David -- Gloor, Susan L -- Vigers, Guy -- Morales, Tony -- Aliagas, Ignacio -- Liu, Bonnie -- Sideris, Steve -- Hoeflich, Klaus P -- Jaiswal, Bijay S -- Seshagiri, Somasekar -- Koeppen, Hartmut -- Belvin, Marcia -- Friedman, Lori S -- Malek, Shiva -- England -- Nature. 2010 Mar 18;464(7287):431-5. doi: 10.1038/nature08833. Epub 2010 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genentech, South San Francisco, California 94080, USA. hatzivassiliou.georgia@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20130576" target="_blank"〉PubMed〈/a〉
Keywords:
Adenosine Triphosphate/metabolism
;
Animals
;
Benzamides/pharmacology
;
Cell Line
;
Cell Membrane/drug effects/metabolism
;
Cell Proliferation/drug effects
;
Diphenylamine/analogs & derivatives/pharmacology
;
Enzyme Activation/drug effects
;
Extracellular Signal-Regulated MAP Kinases/metabolism
;
Humans
;
Indenes/pharmacology
;
Indoles/pharmacology
;
MAP Kinase Signaling System/*drug effects
;
Mice
;
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism
;
Neoplasms/drug therapy/enzymology/metabolism/*pathology
;
Protein Kinase Inhibitors/*pharmacology/therapeutic use
;
Protein Multimerization
;
Protein Structure, Tertiary
;
Protein Transport/drug effects
;
Proto-Oncogene Proteins/genetics/metabolism
;
Proto-Oncogene Proteins B-raf/antagonists &
;
inhibitors/chemistry/genetics/metabolism
;
Proto-Oncogene Proteins c-raf/deficiency/genetics/metabolism
;
Pyrazoles/pharmacology
;
Sulfonamides/pharmacology
;
Xenograft Model Antitumor Assays
;
raf Kinases/*antagonists & inhibitors/chemistry/genetics/*metabolism
;
ras Proteins/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
