RG7204 (PLX4032), a Selective BRAFV600E Inhibitor, Displays Potent Antitumor Activity in Preclinical Melanoma Models

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-07, Vol.70 (13), p.5518-5527
• Main Authors: HONG YANG, HIGGINS, Brian, SCHOSTACK, Kathleen, SIMCOX, Mary Ellen, HEIMBROOK, David, BOLLAG, Gideon, FEI SU, KOLINSKY, Kenneth, PACKMAN, Kathryn, ZENAIDA GO, IYER, Raman, KOLIS, Stanley, ZHAO, Sylvia, LEE, Richard, GRIPPO, Joseph F
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Cycle - drug effects; Cell Growth Processes - drug effects; Cell Line, Tumor; Dermatology; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; Indoles - pharmacology; MAP Kinase Kinase Kinases - metabolism; Medical sciences; Melanoma - drug therapy; Melanoma - enzymology; Melanoma - genetics; Melanoma - pathology; Mice; Mice, Nude; Mutation; Pharmacology. Drug treatments; Phosphorylation; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Sulfonamides - pharmacology; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0646

The BRAF(V600E) mutation is common in several human cancers, especially melanoma. RG7204 (PLX4032) is a small-molecule inhibitor of BRAF(V600E) kinase activity that is in phase II and phase III clinical testing. Here, we report a preclinical characterization of the antitumor activity of RG7204 using established in vitro and in vivo models of malignant melanoma. RG7204 potently inhibited proliferation and mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and ERK phosphorylation in a panel of tumor cell lines, including melanoma cell lines expressing BRAF(V600E) or other mutant BRAF proteins altered at codon 600. In contrast, RG7204 lacked activity in cell lines that express wild-type BRAF or non-V600 mutations. In several tumor xenograft models of BRAF(V600E)-expressing melanoma, we found that RG7204 treatment caused partial or complete tumor regressions and improved animal survival, in a dose-dependent manner. There was no toxicity observed in any dose group in any of the in vivo models tested. Our findings offer evidence of the potent antitumor activity of RG7204 against melanomas harboring the mutant BRAF(V600E) gene.