Journal Article

RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

Yen, Ivana, Liu, Bonnie, Seshagiri, Somasekar, Aliagas, Ignacio, Brandhuber, Barbara J., Belvin, Marcia, Gloor, Susan L., Anderson, Daniel J., Song, Kyung, Malek, Shiva, Alvarado, Ryan, Koeppen, Hartmut, Hatzivassiliou, Georgia, Vigers, Guy, Hoeflich, Klaus P., Ludlam, Mary J. C., Sideris, Steve, Morales, Tony, Jaiswal, Bijay S., Friedman, Lori S., Stokoe, David

2010

Overview

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 . The RAS–RAF signalling pathway is an attractive target for drug development in oncology, and several RAF inhibitors are being tested in clinical trials. Here and in an accompanying paper, RAF inhibitors are shown to have opposing roles, functioning as either inhibitors or activators of RAF depending on the cellular context and mutational status of RAF. The mechanistic basis for these opposing roles is dissected. The results have implications for the clinical use of these inhibitors and for the design of kinase inhibitors. 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 1 . 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 2 , 3 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/395 / 631/80/86 / 631/92/609 / Adenosine Triphosphate - metabolism / Animal tumors. Experimental tumors / Animals / Antineoplastic agents / ATP / Benzamides - pharmacology / Biological and medical sciences / Cell Line / Cell Membrane - drug effects / Cell Membrane - metabolism / Cell Proliferation - drug effects / Cellular / Cellular signal transduction / Clinical trials / Competition / Dimerization / Diphenylamine - analogs & derivatives / Diphenylamine - pharmacology / Enzyme Activation - drug effects / Enzymes / Experimental tumors, general aspects / Extracellular Signal-Regulated MAP Kinases - metabolism / General aspects / Genetic aspects / Growth / Humanities and Social Sciences / Humans / Indenes - pharmacology / Indoles - pharmacology / Inhibitors / Kinases / letter / MAP Kinase Signaling System - drug effects / Medical sciences / Melanoma / Mice / Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors / Mitogen-Activated Protein Kinase Kinases - metabolism / Mitogen-activated protein kinases / multidisciplinary / Neoplasms - drug therapy / Neoplasms - enzymology / Neoplasms - metabolism / Neoplasms - pathology / Pathways / Pharmacology. Drug treatments / Physiological aspects / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein Multimerization / Protein Structure, Tertiary / Protein Transport - drug effects / Proteins / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - chemistry / Proto-Oncogene Proteins B-raf - genetics / Proto-Oncogene Proteins B-raf - metabolism / Proto-Oncogene Proteins c-raf - deficiency / Proto-Oncogene Proteins c-raf - genetics / Proto-Oncogene Proteins c-raf - metabolism / Proto-Oncogene Proteins p21(ras) / Pyrazoles - pharmacology / raf Kinases - antagonists & inhibitors / raf Kinases - chemistry / raf Kinases - genetics / raf Kinases - metabolism / Ras genes / ras Proteins - genetics / ras Proteins - metabolism / Science / Science (multidisciplinary) / Signalling / Sulfonamides - pharmacology / Tumors / Tumours / Xenograft Model Antitumor Assays