What have we learned about multidrug resistance in cancer?

Multidrug resistance (MDR) in cancer is a barrier to effective treatment with traditional chemotherapy and will eventually result, in most cases, in the failure of more targeted chemotherapy as well. Drug resistance has been studied by analyzing cultured cancer cells selected for resistance to anti‐cancer drugs, or engineered to have altered expression of specific genes. Changes in expression of a large number of gene products and pathways have been associated with MDR in vitro including ATP‐dependent drug efflux pumps, such as ABCB1 (P‐glycoprotein, MDR1), ABCC1 (MRP), and ABCG2 (BCRP), uptake transporters, pathways that sequester drugs, altered metabolism, heat shock proteins, altered apoptotic pathways, and variations in growth promoting, and cell cycle pathways. Given the expression of the broad spectrum multidrug efflux pump P‐glycoprotein in many cancers in vivo as well as in vitro , we have targeted this gene product which renders MDR cells highly sensitive to some chemical compounds. In addition, we have explored the role of 380 different MDR gene products using a Taqman Low Density Array (TLDA) assay to measure mRNA levels in clinical cancer samples. Strikingly, most in vitro cancer cell models do not recapitulate MDR gene expression patterns seen in primary cancers, but some patterns of MDR gene expression are associated with poor prognosis in ovarian and liver cancer.