Human drug transporters and taxane resistance

A189 Treatment with the taxanes (Paclitaxel or Docetaxel) is often the therapy of choice for women with breast cancer. In most cases, taxanes arrest cell proliferation at the G2/M phase and cause cell death. However, some tumors develop resistance during the course of treatment, which is a major concern for both patients and physicians. Several mechanisms of resistance have been proposed to explain how resistance to the taxanes occurs, but this phenomenon remains incompletely understood. Our preliminary gene expression microarray and western blot data in taxane sensitive and resistant MDA-MB-231 cells suggest that the expression of human drug transporter genes are significantly altered in our model of acquired resistance, despite the selection occurring in the presence of verapamil, a known P-glycoprotein inhibitor. Our gene expression data show significant differential upregulation of ABCB1 (43.2 fold; p=0.00003) in Docetaxel resistant cells and in Paclitaxel resistant cells (2.8 fold; p=0.002) each selected in the presence of 1 µM verapamil. In addition, 10 other members of the ABC transporter family in Paclitaxel resistant cells and 62 SLC family members were significantly differentially expressed. In our Docetaxel resistant cells, 8 ABC family members and 58 SLC transporters were differentially expressed. Only 5 ABC family transporters and 19 SLC family transporter expression are commonly overexpressed between our two resistant phenotypes. Neither of our resistant phenotypes express BCRP. Despite its overexpression, data from studies using siRNA directed at silencing P-glycoprotein suggest that P-glycoprotein does not significantly affect the resistant phenotype. These data suggests that indeed several and not just one transmembrane multidrug resistant transporter may be used to support each of the resistance phenotypes. We have also found that cross resistance occurs for Docetaxel resistant cells (these cells are also resistant to Paclitaxel) but full cross resistance does not occur for Paclitaxel resistant cells (retain sensitivity to Docetaxel drug). This suggests that the resistance pathways used by each drug may not be redundant. Given our preliminary data, we propose to further investigate the role of transmembrane transporters in conferring resistance to the taxanes in both MDA-MB-231 and MCF7 breast cancer cells and compare them to levels seen in clinical samples of human breast cancer tissue from responsive and non-responsive patients. Our studies will assist in our understanding of how different classes of transporters contribute to the resistance phenotype. Ultimately our studies aim not only to improve our understanding of taxane resistance on the bench but may also provide the framework for formulation of novel therapies that may improve the success of taxane therapy in women with breast cancer in the clinic.