Hatzivassiliou, G, Haling, JR, Chen, H, Song, K, Price, S, Heald, R, Hewitt, JFM, Zak, M, Peck, A, Orr, C, Merchant, M, Hoeflich, KP, Chan, J, Luoh, S, Anderson, DJ, Ludlam, MJC, Wiesmann, C, Ultsch, M, Friedman, LS, Malek, S and Belvin, M (2013) Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature, 501 (7466). pp. 232-236. ISSN 0028-08361476-4687

Abstract

KRAS and BRAF activating mutations drive tumorigenesis through constitutive activation of the MAPK pathway. As these tumours represent an area of high unmet medical need, multiple allosteric MEK inhibitors, which inhibit MAPK signalling in both genotypes, are being tested in clinical trials. Impressive single-agent activity in BRAF-mutant melanoma has been observed; however, efficacy has been far less robust in KRAS-mutant disease. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours, different mechanisms of inhibition are required for optimal antitumour activity in each genotype. Structural and functional analysis illustrates that MEK inhibitors with superior efficacy in KRAS-driven tumours (GDC-0623 and G-573, the former currently in phase I clinical trials) form a strong hydrogen-bond interaction with S212 in MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. Conversely, potent inhibition of active, phosphorylated MEK is required for strong inhibition of the MAPK pathway in BRAF-mutant tumours, resulting in superior efficacy in this genotype with GDC-0973 (also known as cobimetinib), a MEK inhibitor currently in phase III clinical trials. Our study highlights that differences in the activation state of MEK in KRAS-mutant tumours versus BRAF-mutant tumours can be exploited through the design of inhibitors that uniquely target these distinct activation states of MEK. These inhibitors are currently being evaluated in clinical trials to determine whether improvements in therapeutic index within KRAS versus BRAF preclinical models translate to improved clinical responses in patients. 2013 Macmillan Publishers Limited. All rights reserved

Item Type:	Article
Additional Information:	pubid: 143 nvp_institute: NIBR contributor_address: (Hatzivassiliou, Song, Orr, Merchant, Hoeflich, Chan, Luoh, Friedman, Belvin) Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States (Haling, Peck, Malek) Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States (Chen, Zak) Department of Discovery Chemistry, Genentech, Inc., 1DNAWay, South San Francisco, CA 94080, United States (Price, Heald, Hewitt) Argenta, 8/9 Spire Green Centre, Flex-Meadow, Harlow, Essex CM195TR, United Kingdom (Anderson, Ludlam) Department of Discovery Oncology, Genentech, Inc., 1DNAWay, South San Francisco, CA 94080, United States (Wiesmann, Ultsch) Department of Structural Biology, Genentech, Inc., 1 DNAWay, South San Francisco, CA 94080, United States (Hewitt) WestCHEM, School of Chemistry, University of Glasgow, University Avenue, Glasgow G12 8QQ, United Kingdom (Peck) MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 OXY, United Kingdom (Wiesmann) Novartis Institutes for Biomedical Research, Fabrikstrasse 16, CH-4002 Basel, Switzerland (Ludlam) Cairn Biosciences Inc., 3534 24th Street, San Francisco, CA 94110, United States (Anderson) Cleave Biosciences, 866 Malcolm Road suite 100, Burlingame, CA 94010, United States
Date Deposited:	13 Oct 2015 13:12
Last Modified:	06 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/21977