Journal article
Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
G Bollag, P Hirth, J Tsai, J Zhang, PN Ibrahim, H Cho, W Spevak, C Zhang, Y Zhang, G Habets, EA Burton, B Wong, G Tsang, BL West, B Powell, R Shellooe, A Marimuthu, H Nguyen, KYJ Zhang, DR Artis Show all
Nature | Published : 2010
DOI: 10.1038/nature09454
Abstract
B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selecti..
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Awarded by National Institutes of Health
Funding Acknowledgements
We thank L. Andries and M. Knaapen from HistoGeneX for evaluating paired biopsies, and also our colleagues at the Molecular Imaging Research division of Charles River Labs for conducting the xenograft studies. We also thank D. Heimbrook, S. Cheng, L. Burdette and B. Lestini for helpful comments on the manuscript. This research was funded in part by NIH grants to K.L.N. G.A.M. is supported by a Weary Dunlop Fellowship of the Cancer Council of Victoria.