Oncogenic mutations in the protein kinase B-Raf are found in many human cancers; many melanomas are associated with the V600E mutation in B-Raf. Because melanoma tumors depend on the Raf-MEK-ERK pathway, the development of inhibitors of mutant B-Raf is likely to provide effective therapies to target these types of melanomas. Bollag et al. characterized the small-molecule inhibitor PLX4032, which selectively targets B-Raf(V600E). PLX4032 was discovered through a scaffold-based method for designing drugs, and the authors solved the crystal structure of PLX4032 bound to B-Raf(V600E), which suggested how PLX4032 affected the dimerization of B-Raf. PLX4032 inhibited the Raf-MEK-ERK pathway in cell lines that contained B-Raf(V600E) but not in cells that contained wild-type B-Raf. PLX4032 inhibited tumor growth in a mouse model of colorectal cancer and caused tumor regression at higher concentrations. Preclinical studies established the safety of the drug, and phase I trials were performed in patients with metastatic melanoma. PLX4032 resulted in partial responses (measurable tumor regression) in the majority of patients with B-Raf mutations, but not in patients without mutant B-Raf. Further studies involved the analysis of biopsies taken from patients before and two weeks after treatment with the inhibitor. Immunohistochemical analysis showed that PLX4032 caused a reduction in the abundance of cytoplasmic phosphorylated ERK (pERK). The decreases in pERK abundance correlated well with outcome; those patients with tumor regression showed more than 80% inhibition in the abundance of cytoplasmic pERK. Side effects included the development of cutaneous squamous cell carcinoma, which was treatable, and the durability of the response is still under evaluation. The authors suggest that combining PLX4032 with other treatments will improve options for patients with mutant B-Raf melanoma.
G. Bollag, P. Hirth, J. Tsai, J. Zhang, P. N. Ibrahim, H. Cho, W. Spevak, C. Zhang, Y. Zhang, G. Habets, E. A. Burton, B. Wong, G. Tsang, B. L. West, B. Powell, R. Shellooe, A. Marimuthu, H. Nguyen, K. Y. J. Zhang, D. R. Artis, J. Schlessinger, F. Su, B. Higgins, R. Iyer, K. D’Andrea, A. Koehler, M. Stumm, P. S. Lin, R. J. Lee, J. Grippo, I. Puzanov, K. B. Kim, A. Ribas, G. A. McArthur, J. A. Sosman, P. B. Chapman, K. T. Flaherty, X. Xu, K. L. Nathanson, K. Nolop, Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010). [PubMed]