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

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, Brian L. West, Ben Powell, Rafe Shellooe, Adhirai Marimuthu, Hoa Nguyen, Kam Y. J. Zhang, Dean R. Artis, Joseph Schlessinger, Fei Su, Brian Higgins, Raman Iyer, Kurt D’Andrea, Astrid Koehler, Michael Stumm, Paul S. Lin, Richard J. Lee, Joseph Grippo, Igor Puzanov, Kevin B. Kim, Antoni Ribas, Grant A. McArthur, Jeffrey A. Sosman, Paul B. Chapman, Keith T. Flaherty, Xiaowei Xu, Katherine L. Nathanson and Keith Nolop
Additional contact information
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

Nature, 2010, vol. 467, issue 7315, 596-599

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.

Date: 2010
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DOI: 10.1038/nature09454

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