Scientists establish database of genes associated with cancer drug resistance

Scientists at the National Cancer Institute (NCI), a part of the National Institutes of Health, have created a database of information about a group of genes associated with multidrug resistance in cancerous tumors. The research, published in the August 24, 2004, issue of Cancer Cell*, details the gene expression of a 48-member family of proteins called ABC transporters. The NCI scientists identified associations between expression of individual ABC transporters in cancer cells and resistance to specific drugs.

Though ABC transporters are primarily associated with drug resistance, the researchers report an association between some of these proteins and an increase in effectiveness of some cancer drugs. Their database should serve as a starting point for research into novel therapies designed either to evade or exploit the action of ABC transporters.

ABC transport proteins are embedded in the cell membrane and regulate traffic of many molecules, including hormones, lipids, and drugs, in and out of the cell. Because they transport toxic materials out of cells, many of these 48 proteins confer resistance to cancer drugs in humans. The study’s lead authors were Jean-Philippe Annereau, Ph.D., and Gergely Szakács, M.D., Ph.D., both visiting fellows at NCI’s Center for Cancer Research (CCR). Szakács said, “Multidrug resistance is a major barrier to effective cancer chemotherapy, and even low levels of resistance can have a significant impact on the efficacy of chemotherapy.”

Though these proteins have major implications for the treatment of cancer, previous studies had characterized only 17 of them using much less sensitive techniques. Szakács and Annereau studied the ABC transporters in a group of cancer cell lines called the NCI-60 cells, which includes leukemias, melanomas, and ovarian, breast, prostate, lung, renal, and colon cancers.

They used real-time polymerase chain reaction to detect and quantify the expression of ABC transporter genes as messenger RNA in these cells. With help from collaborators in the laboratory of John Weinstein, M.D., Ph.D., also in CCR, the researchers found statistical correlations between tests of the cell lines’ sensitivity to cancer drugs and these cells’ expression of ABC transporters. Further tests, such as measuring changes in cell growth to evaluate the cells’ response to the drugs, supported the statistical correlations.

Analysis of 68,592 ABC gene and drug relationships yielded 131 strongly inverse-correlated pairs–that is, in these 131 cases, cells’ ABC gene expression was strongly correlated with decreased sensitivity to the drug. According to Michael Gottesman, M.D., one of the paper’s senior authors and chief of the Laboratory of Cell Biology in CCR, “These results indicate that some of the ABC transporters whose function remains unknown can influence the response of cells to cancer treatment.”

Gottesman, Szakács, and colleagues hope this data will be used to find commonalities in compounds transported by MDR1, one of the ABC proteins most strongly associated with multidrug resistance. With this information, they could begin developing a drug to undermine MDR1’s ability to transport drugs out of the cell.

Expression of some ABC transporters, most notably MDR1, caused an increase in cancer cells’ sensitivity to some drugs. This increase was unexpected, as MDR1 is perhaps the best-known multidrug resistance protein. The researchers advocate further research in order to discover additional compounds that interact in this way with MDR1 and other ABC transporters.