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An NCI Team Links ABC Transporter-Protein Expression and Cancer-Cell Drug Response

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National Cancer Institute scientists recently created a gene-expression database for ABC transport proteins that they hope will be compared to a constantly growing second database of cancer-drug responses.

Their research links cancer-cell drug resistance — and occasional sensitivity — to 1,429 compounds in the huge NCI-60 Drug Screen database with the expression of each of the 48 ABC protein-family members.

Details of the study, which appears in the Aug. 22 issue of Cancer Cell, may point to targets for drug development, said Gergely Szakács of the NCI’s Center for Cancer Research.

“Everyone thinks of ABC transporters as protective measures” because the plasma-membrane members of this family are all known as exporters that keep intracellular drug levels low, said Szakács. “We not only find compounds against which ABC transporters provide protection, but we have found compounds that are more active in cells that are otherwise protected by ABC transporters,” he added.

The gene-expression data, gathered using real-time quantitative PCR, follows the path of previous ABC research by John Weinstein and colleagues at the NCI’s CCR Laboratory of Molecular Pharmacology, who used older and less-sensitive microarrays to catalogue the expression of 17 ABC-transport proteins.

The NCI chose 60 cell lines, the “NCI 60,” with the aim of studying their response to practically all the drugs available, said lead author Szakács. He and Weinstein both used the NCI 60 in their studies.

Szakács and colleagues compared two matrices: one containing the cell lines’ response to 1,429 drugs; and the other containing their own gene-expression profile of each of the cell lines. Computer analysis of the 68,592 pair-wise relations resulted in 131 inverse correlations, while a few yielded a direct correlation between ABC expression and drug resistance.

The current research includes data for a small subset of a very large and growing drug-response database that the NCI has been building since the 1990s. Szakács estimates that information about cancer-cell response to more than 100,000 compounds is available in the NCI database.

An NCI Developmental Therapeutics Program spokesperson said that the database also contains information about an approximately equal number of proprietary compounds as well. Qualifying researchers can send the Institute samples for testing, with results remaining confidential or becoming public knowledge after two years, should the researcher so desire.

The function of ABC proteins in normal cells might also interest drug makers, said Szakács. Many of the proteins operate at boundaries like the blood-brain barrier and the gut, and understanding their interaction with drugs may help control how some compounds are distributed throughout the body.

The team has not been contacted by drug development companies concerning the recent study, said Szakács.

A spokesperson for the NCI DTP said that since the drug-response database was established about 10 years ago, it probably contains few compounds that have been brought to market. She said several of the compounds were likely moving through the approval process, especially those in the confidential section of the database.

The study, ABC expression data and a matrix analysis tool are available at discover.nci.nih.gov/ABC.

— CW

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