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. ArtisJoseph Schlessinger, Fei Su, Brian Higgins, Raman Iyer, Kurt Dandrea, 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, Keith Nolop

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1309 Scopus citations


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 selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.

Original languageEnglish (US)
Pages (from-to)596-599
Number of pages4
Issue number7315
StatePublished - Sep 30 2010

ASJC Scopus subject areas

  • General


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