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Spotlight on Molecular Profiling

Predicting cisplatin and trabectedin drug sensitivity in ovarian and colon cancers

¹ Laboratory of Molecular Pharmacology and ² Laboratory of Pathology, Center for Cancer Research and ³ Mathematical and Statistical Computing Laboratory, Center for Information Technology, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Yves Pommier, National Cancer Institute, Building 37, Room 5068, Bethesda, MD 20892. Phone: 301-496-5944; Fax: 301-402-0752. E-mail: pommier{at}nih.gov

Abstract

Molecular profiling of markers involved in the activity of chemotherapeutic agents can shed light on the successes and failures of treatment in patients and can also provide a basis for individualization of therapy. Toward those ends, we have used reverse-phase protein lysate microarrays to evaluate expression of protein components of the nucleotide excision repair (NER) pathways. Those pathways strongly influence the anticancer activities of numerous drugs, including those that are the focus here, cisplatin and ecteinascidin 743 (Et-743; Yondelis, Trabectedin). Cisplatin is generally more active in cell types deficient in NER, whereas Et-743 tends to be less active in those cells. We measured protein expression and sensitivity to those drugs in 17 human ovarian and colon cancer cell lines (13 of them from the NCI-60 panel) and five xeroderma pigmentosum (XP) patient cell types, each containing a different NER defect. Of the NER proteins giving reliable signals, XPF and XPG showed the highest correlations of protein expression with drug activity across all three tissue-of-origin groups. When we compared protein expression data with mRNA expression data from Affymetrix U133A chips, we found no consistent correlation between the two across the cell lines studied, which reinforces the conclusion that protein measurements can give more interpretable mechanistic information than can transcript measurements. The work reported here provides motivation for larger proteomic studies with more cell types focused on potential biomarkers in additional pharmacologically pertinent pathways. [Mol Cancer Ther 2008;7(1):10–8]

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

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.

Note: E.C. Kohn and Y. Pommier contributed equally to this manuscript.

⁴ http://www.pharmamar.com/en/pipeline/yondelis.cfm

⁵ Available at http://abs.cit.nih.gov/pscan.

⁶ Available at http://discover.nci.nih.gov.

⁷ Derived from http://discover.nci.nih.gov/cellminer.

Received 3/19/07; revised 9/28/07; accepted 12/ 4/07.