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Parallel selection of chemotherapy-resistant cell lines to illuminate mechanisms of drug resistance in human tumors : Abstract of paper from the IMPAKT Breast Cancer Conference

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Abstract

Treatment of cancer often involves the use of chemotherapeutic agents that preferentially target tumor cells. The idea behind personalized medicine is to characterize differences between individual cancer cases that will and to direct the therapy to those most likely to respond. This will require the identification of reliable predictive biomarkers for each drug. Currently, we are developing a framework for systematic biomarker discovery by using a combination of gene expression and CGH arrays to keep track of consistent changes that take place during resistance acquisition in cell lines towards two anti-cancer drugs: doxorubicin and paclitaxel. By monitoring changes at two different levels (DNA and RNA) of the genome and developing multiple cell lines developing resistance against the same drug under identical conditions, we were able to separate relevant changes from spurious ones and thus reducing the noise of the experimental system. Doxorubicin is an anthracycline that exerts its anticancer effect through intercalation into DNA and inhibition of topoisomerase II, whereas paclitaxel stabilizes microtubules and disrupts the mitotic spindle. We use expression and copy number data from two cell lines, MDA-231 and MCF-7, that were grown in the presence of doxorubicin (n=16) or paclitaxel (n=11), vehicle control (n=2). We have observed a distinct pattern of chemotherapy-induced genomic changes. Doxorubicin-induced changes involve greater genomic rearrangements than paclitaxel, which is with accordance to their mode of action. Our findings are validated on already existing gene expression profiles of patient cohorts treated with the drugs in question, and the most promising ones will be chosen for functional validation by RNAi knock down. Successful validation will improve understanding of drug resistance mechanisms, suggest future drug targets, and enable more efficacious treatment of cancer patients.