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

Author

Listed:
  • Georgia Hatzivassiliou

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Jacob R. Haling

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Huifen Chen

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Kyung Song

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Steve Price

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

  • Robert Heald

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

  • Joanne F. M. Hewitt

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

  • Mark Zak

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Ariana Peck

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
    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.).)

  • Christine Orr

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Mark Merchant

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Klaus P. Hoeflich

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Jocelyn Chan

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Shiuh-Ming Luoh

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Daniel J. Anderson

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
    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.).)

  • Mary J. C. Ludlam

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
    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.).)

  • Christian Wiesmann

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
    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.).)

  • Mark Ultsch

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Lori S. Friedman

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Shiva Malek

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

  • Marcia Belvin

    (Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA)

Abstract

The mechanism of action of three different allosteric MEK inhibitors that target the MAP kinase pathway is investigated, and their efficacy is shown to be explained by the distinct mechanisms regulating MEK activation in KRAS- versus BRAF-driven tumours; this work provides a rationale for designing more effective cancer therapies for these common genetic subtypes of cancer.

Suggested Citation

  • Georgia Hatzivassiliou & Jacob R. Haling & Huifen Chen & Kyung Song & Steve Price & Robert Heald & Joanne F. M. Hewitt & Mark Zak & Ariana Peck & Christine Orr & Mark Merchant & Klaus P. Hoeflich & Jo, 2013. "Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers," Nature, Nature, vol. 501(7466), pages 232-236, September.
    • Handle: RePEc:nat:nature:v:501:y:2013:i:7466:d:10.1038_nature12441
    DOI: 10.1038/nature12441
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    Cited by:

    1. Nishanth Ulhas Nair & Patricia Greninger & Xiaohu Zhang & Adam A. Friedman & Arnaud Amzallag & Eliane Cortez & Avinash Das Sahu & Joo Sang Lee & Anahita Dastur & Regina K. Egan & Ellen Murchie & Miche, 2023. "A landscape of response to drug combinations in non-small cell lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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