COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

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 Caponigro, Haley Hieronymus, Ryan R. Murray, Kourosh Salehi-Ashtiani, David E. Hill, Marc Vidal, Jean J. Zhao, Xiaoping Yang, Ozan Alkan, Sungjoon Kim, Jennifer L. Harris, Christopher J. Wilson, Vic E. Myer, Peter M. Finan, David E. Root, Thomas M. Roberts, Todd Golub, Keith T. Flaherty, Reinhard Dummer, Barbara L. Weber, William R. Sellers, Robert Schlegel, Jennifer A. Wargo, William C. Hahn and Levi A. Garraway ()
Additional contact information
Cory M. Johannessen: Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
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
Sapana R. Thomas: Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
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
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
Giordano Caponigro: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
Haley Hieronymus: Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center
Ryan R. Murray: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
Kourosh Salehi-Ashtiani: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
David E. Hill: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
Marc Vidal: Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute
Jean J. Zhao: Dana-Farber Cancer Institute
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
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
Levi A. Garraway: Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center

Nature, 2010, vol. 468, issue 7326, 968-972

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.

Date: 2010
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DOI: 10.1038/nature09627

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