A novel B-RAF inhibitor blocks interleukin-8 (IL-8) synthesis in human melanoma xenografts, revealing IL-8 as a potential pharmacodynamic biomarker.
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| Abstract |
B-RAF mutations have been identified in the majority of melanoma and a large fraction of colorectal and papillary thyroid carcinoma. Drug discovery efforts targeting mutated B-RAF have yielded several interesting molecules, and currently, three compounds are undergoing clinical evaluation. Inhibition of B-RAF in animal models leads to a slowing of tumor growth and, in some cases, tumor reduction. Described within is a novel series of diaryl imidazoles with potent, single-digit nanomolar, anti-B-RAF activity. One compound from this series has been detailed here and has been shown to block B-RAF(V600E)-dependent extracellular signal-regulated kinase 1/2 phosphorylation in SK-MEL-28 melanoma cells as well as soft agar colony formation and proliferation. Importantly, interleukin-8 (IL-8) was identified by quantitative real-time PCR and ELISA as a product of the elevated mitogen-activated protein kinase signaling in these cells. Plasma concentrations of IL-8 in mice bearing melanoma xenografts were significantly reduced following exposure to B-RAF inhibitors. Taken together, these data suggest that IL-8 could serve as a tractable clinical biomarker.
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| Authors | Shelby Crawford, Daniel Belajic, Jianmei Wei, Jason P Riley, Paul J Dunford, Scott Bembenek, Anne Fourie, James P Edwards, Lars Karlsson, Anders Brunmark, Ronald L Wolin, Jonathan M Blevitt |
| Journal | Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 3 Pg. 492-9 (Mar 2008) ISSN: 1535-7163 [Print] United States |
| PMID | 18347137 (Publication Type: Journal Article) |
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