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Spotlight on Molecular Profiling

In vitro differential sensitivity of melanomas to phenothiazines is based on the presence of codon 600 BRAF mutation

¹ Genomics and Bioinformatics Group, Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland; ² Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, United Kingdom; ³ School of Pharmacy, Department of Clinical Pharmacy, University of California-San Francisco, San Francisco, California; ⁴ Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California; and ⁵ Program of Pharmacogenomics, Department of Pharmacology and the Comprehensive Cancer Center, Ohio State University, Columbus, Ohio

Requests for reprints: Ogechi N. Ikediobi, School of Pharmacy, Department of Clinical Pharmacy, University of California-San Francisco, 3333 California Street, Box 0613, San Francisco, CA 94118. Phone: 415-476-1230. E-mail: ikediobio{at}pharmacy.ucsf.edu

Abstract

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. We previously sequenced 24 cancer genes in those cell lines. Eleven of the genes were found to be mutated in three or more of the lines. Using a pharmacogenomic approach, we analyzed the relationship between drug activity and mutations in those 11 genes (APC, RB1, KRAS, NRAS, BRAF, PIK3CA, PTEN, STK11, MADH4, TP53, and CDKN2A). That analysis identified an association between mutation in BRAF and the antiproliferative potential of phenothiazine compounds. Phenothiazines have been used as antipsychotics and as adjunct antiemetics during cancer chemotherapy and more recently have been reported to have anticancer properties. However, to date, the anticancer mechanism of action of phenothiazines has not been elucidated. To follow up on the initial pharmacologic observations in the NCI-60 screen, we did pharmacologic experiments on 11 of the NCI-60 cell lines and, prospectively, on an additional 24 lines. The studies provide evidence that BRAF mutation (codon 600) in melanoma as opposed to RAS mutation is predictive of an increase in sensitivity to phenothiazines as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay (Wilcoxon P = 0.007). That pattern of increased sensitivity to phenothiazines based on the presence of codon 600 BRAF mutation may be unique to melanomas, as we do not observe it in a panel of colorectal cancers. The findings reported here have potential implications for the use of phenothiazines in the treatment of V600E BRAF mutant melanoma. [Mol Cancer Ther 2008;7(6):1337–46]

Grant support: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and Wellcome Trust.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ http://www.sanger.ac.uk/genetics/CGP/Census

⁷ http://dtp.nci.nih.gov/docs/cancer/cancer_data.html

⁸ http://www.r-project.org

⁹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

¹⁰ http://www.sanger.ac.uk/CGP/COSMIC

Received 2/ 1/08; revised 4/15/08; accepted 4/18/08.