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Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers

Nature volume 501, pages 232–236 (2013)Cite this article

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An Erratum to this article was published on 02 October 2013

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 disease1. Here we show that, owing to distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours2,3, 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.

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Figure 1: Allosteric MEK inhibitors show distinct relative potencies in KRAS-mutant and BRAF-mutant cancer models.
Figure 2: MEK inhibitor efficacy in KRAS-mutant models correlates with the ability to block feedback-induced phosphorylation of MEK by RAF.
Figure 3: Distinct inhibitor interactions with MEK determine their individual effects on RAF–MEK complex formation, MEK activation and inhibition of ERK phosphorylation.
Figure 4: Potency of MEK inhibitors in BRAF-mutant versus KRAS-mutant tumours correlates with high inhibitor binding affinity against dually phosphorylated MEK (S218/S222) compared to un-phosphorylated MEK.

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Protein Data Bank

Data deposits

The structure of the MEK1:GDC-0973 complex has been deposited with the PDB and assigned accession code 4LMN.

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Acknowledgements

The authors would like to acknowledge the Genentech IVCC group, IVP dosing group, as well as B. Liu and I. Yen and for technical support. SSRL is supported by the Department of Energy, the National Institutes of Health, the National Institute of General Medical Sciences and the National Center for Research Resources.

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Author notes

  1. Joanne F. M. Hewitt, Ariana Peck, Daniel J. Anderson, Mary J. C. Ludlam & Christian Wiesmann

    Present address: Present addresses: WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, UK (J.F.M.H.); MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 OXY, UK (A.P.); Novartis Institutes for Biomedical Research, Fabrikstrasse 16, CH-4002 Basel, Switzerland (C.W.); Cairn Biosciences Inc., 3534 24th Street, San Francisco, California 94110, USA (M.J.C.L.); Cleave Biosciences, 866 Malcolm Road suite 100, Burlingame, California 94010, USA (D.J.A.).,

Authors and Affiliations

  1. Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Georgia Hatzivassiliou, Kyung Song, Christine Orr, Mark Merchant, Klaus P. Hoeflich, Jocelyn Chan, Shiuh-Ming Luoh, Lori S. Friedman & Marcia Belvin

  2. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Jacob R. Haling, Ariana Peck & Shiva Malek

  3. Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Huifen Chen & Mark Zak

  4. Argenta, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK,

    Steve Price, Robert Heald & Joanne F. M. Hewitt

  5. Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Daniel J. Anderson & Mary J. C. Ludlam

  6. Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA,

    Christian Wiesmann & Mark Ultsch

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  1. Georgia Hatzivassiliou
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Contributions

J.R.H., K.S., S-M.L., J.C., A.P., C.O. J.F.M.H., D.J.A., M.J.C.L., M.Z. and M.U. performed the experiments; M.M., S.P., R.H., C.W., M.Z. and K.P.H. analysed data; L.S.F. provided comments; G.H., J.R.H., H.C., S.M. and M.B. directed the studies, analysed data, and wrote the manuscript.

Corresponding authors

Correspondence to Georgia Hatzivassiliou or Marcia Belvin.

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The authors were all employees of Genentech or Argenta at the time that the work was carried out.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Figures 1-13 and Supplementary Tables 1-3. This file was replaced on September 11, as Supplementary Figure 7 was corrupted and Supplementary Figures 12 and 13 were missing from the original file posted on line. (PDF 10886 kb)

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Hatzivassiliou, G., Haling, J., Chen, H. et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature 501, 232–236 (2013). https://doi.org/10.1038/nature12441

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