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COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Author

Listed:
  • Cory M. Johannessen

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Jesse S. Boehm

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center)

  • So Young Kim

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
    Present address: Duke Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina 27710, USA (S.Y.K).)

  • Sapana R. Thomas

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Leslie Wardwell

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Laura A. Johnson

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Caroline M. Emery

    (Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Nicolas Stransky

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center)

  • Alexandria P. Cogdill

    (Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA)

  • Jordi Barretina

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Giordano Caponigro

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Haley Hieronymus

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Current address: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA)

  • Ryan R. Murray

    (Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Kourosh Salehi-Ashtiani

    (Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • David E. Hill

    (Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Marc Vidal

    (Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Jean J. Zhao

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Xiaoping Yang

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center)

  • Ozan Alkan

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center)

  • Sungjoon Kim

    (Genomics Institute of the Novartis Research Foundation)

  • Jennifer L. Harris

    (Genomics Institute of the Novartis Research Foundation)

  • Christopher J. Wilson

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Vic E. Myer

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Peter M. Finan

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • David E. Root

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center)

  • Thomas M. Roberts

    (Dana-Farber Cancer Institute)

  • Todd Golub

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Keith T. Flaherty

    (Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA)

  • Reinhard Dummer

    (University Hospital of Zurich, Zurich CH-8091, Switzerland)

  • Barbara L. Weber

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • William R. Sellers

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Robert Schlegel

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Jennifer A. Wargo

    (Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA)

  • William C. Hahn

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
    Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

  • Levi A. Garraway

    (Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
    Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
    Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA)

Abstract

Drug-resistance mechanism in melanoma Clinical trials in melanoma patients carrying B-RAF gene mutations have shown promising results with the B-RAF kinase inhibitor PLX4032, but many patients go on to become resistant. Two papers now uncover possible mechanisms for this resistance. Nazarian et al. report that melanomas can acquire resistance due to mutations of N-RAS or increased expression of PDGFRβ, and Johannessen et al. report resistance due to upregulation of MAP3K8/COT. Each of these mechanisms seems to apply to some patients in the recent PLX4032 trial, yet surprisingly, no secondary B-RAF mutations were observed.

Suggested Citation

  • Cory M. Johannessen & Jesse S. Boehm & So Young Kim & Sapana R. Thomas & Leslie Wardwell & Laura A. Johnson & Caroline M. Emery & Nicolas Stransky & Alexandria P. Cogdill & Jordi Barretina & Giordano , 2010. "COT drives resistance to RAF inhibition through MAP kinase pathway reactivation," Nature, Nature, vol. 468(7326), pages 968-972, December.
    • Handle: RePEc:nat:nature:v:468:y:2010:i:7326:d:10.1038_nature09627
    DOI: 10.1038/nature09627
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    Citations

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    Cited by:

    1. Emily Banks & Vincent Francis & Sheng-Jia Lin & Fares Kharfallah & Vladimir Fonov & Maxime Lévesque & Chanshuai Han & Gopinath Kulasekaran & Marius Tuznik & Armin Bayati & Reem Al-Khater & Fowzan S. A, 2024. "Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Shuo Yang & Jennifer McAdow & Yingqiu Du & Jennifer Trigg & Paul H. Taghert & Aaron N. Johnson, 2022. "Spatiotemporal expression of regulatory kinases directs the transition from mitosis to cellular morphogenesis in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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