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Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma

Author

Listed:
  • Gideon Bollag

    (Plexxikon Inc., 91 Bolivar Drive)

  • Peter Hirth

    (Plexxikon Inc., 91 Bolivar Drive)

  • James Tsai

    (Plexxikon Inc., 91 Bolivar Drive)

  • Jiazhong Zhang

    (Plexxikon Inc., 91 Bolivar Drive)

  • Prabha N. Ibrahim

    (Plexxikon Inc., 91 Bolivar Drive)

  • Hanna Cho

    (Plexxikon Inc., 91 Bolivar Drive)

  • Wayne Spevak

    (Plexxikon Inc., 91 Bolivar Drive)

  • Chao Zhang

    (Plexxikon Inc., 91 Bolivar Drive)

  • Ying Zhang

    (Plexxikon Inc., 91 Bolivar Drive)

  • Gaston Habets

    (Plexxikon Inc., 91 Bolivar Drive)

  • Elizabeth A. Burton

    (Plexxikon Inc., 91 Bolivar Drive)

  • Bernice Wong

    (Plexxikon Inc., 91 Bolivar Drive)

  • Garson Tsang

    (Plexxikon Inc., 91 Bolivar Drive)

  • Brian L. West

    (Plexxikon Inc., 91 Bolivar Drive)

  • Ben Powell

    (Plexxikon Inc., 91 Bolivar Drive)

  • Rafe Shellooe

    (Plexxikon Inc., 91 Bolivar Drive)

  • Adhirai Marimuthu

    (Plexxikon Inc., 91 Bolivar Drive)

  • Hoa Nguyen

    (Plexxikon Inc., 91 Bolivar Drive)

  • Kam Y. J. Zhang

    (Plexxikon Inc., 91 Bolivar Drive)

  • Dean R. Artis

    (Plexxikon Inc., 91 Bolivar Drive)

  • Joseph Schlessinger

    (Yale University)

  • Fei Su

    (Roche Pharmaceuticals)

  • Brian Higgins

    (Roche Pharmaceuticals)

  • Raman Iyer

    (Roche Pharmaceuticals)

  • Kurt D’Andrea

    (Abramson Cancer Center, University of Pennsylvania)

  • Astrid Koehler

    (Roche Pharmaceuticals)

  • Michael Stumm

    (Roche Pharmaceuticals)

  • Paul S. Lin

    (Plexxikon Inc., 91 Bolivar Drive)

  • Richard J. Lee

    (Roche Pharmaceuticals)

  • Joseph Grippo

    (Roche Pharmaceuticals)

  • Igor Puzanov

    (Vanderbilt University)

  • Kevin B. Kim

    (The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard)

  • Antoni Ribas

    (University of California, Los Angeles, 100 UCLA Medical Plaza)

  • Grant A. McArthur

    (Peter MacCallum Cancer Centre)

  • Jeffrey A. Sosman

    (Vanderbilt University)

  • Paul B. Chapman

    (Memorial Sloan Kettering Cancer Center)

  • Keith T. Flaherty

    (Abramson Cancer Center, University of Pennsylvania)

  • Xiaowei Xu

    (Abramson Cancer Center, University of Pennsylvania)

  • Katherine L. Nathanson

    (Abramson Cancer Center, University of Pennsylvania)

  • Keith Nolop

    (Plexxikon Inc., 91 Bolivar Drive)

Abstract

Targeted anticancer drug hope for melanoma PLX4032, a small-molecule inhibitor being developed by Plexxikon of California and Roche Pharmaceuticals in New Jersey ( http://go.nature.com/QnVGQx ), selectively targets B-RAFV600E, a mutant form of the B-RAF protein kinase common in several human cancers. In this issue of Nature, Gideon Bollag and colleagues report promising results for PLX4032 in an early clinical trial in melanoma patients who carry this B-RAF mutation. They also describe the structure and function of PLX4032 and present translational data from a phase I trial to show that clinical efficacy requires a drug concentration that is sufficient to cause a substantial degree of inhibition of the ERK pathway downstream of B-RAF. The study demonstrates how the design of early clinical trials based on the biological mechanisms underlying tumour formation has the potential to speed up the process by which anticancer drugs can reach the clinic.

Suggested Citation

  • Gideon Bollag & Peter Hirth & James Tsai & Jiazhong Zhang & Prabha N. Ibrahim & Hanna Cho & Wayne Spevak & Chao Zhang & Ying Zhang & Gaston Habets & Elizabeth A. Burton & Bernice Wong & Garson Tsang &, 2010. "Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma," Nature, Nature, vol. 467(7315), pages 596-599, September.
    • Handle: RePEc:nat:nature:v:467:y:2010:i:7315:d:10.1038_nature09454
    DOI: 10.1038/nature09454
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    Cited by:

    1. Gaurav Mendiratta & Eugene Ke & Meraj Aziz & David Liarakos & Melinda Tong & Edward C. Stites, 2021. "Cancer gene mutation frequencies for the U.S. population," Nature Communications, Nature, vol. 12(1), pages 1-11, December.

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