A Dual-Action Approach to Multidrug-Resistant Breast Cancer: Prophylaxis to Ensure Therapeutic Effect

The development of drug resistance represents a formidable barrier to the successful treatment of breast cancer. Although some cancers such as melanoma can be intrinsically resistant, many cancers acquire resistance through selection pressure in the face of adversity, e.g., chemotherapy. One of the most consistent features of drug resistance is overexpression of Pglycoprotein P-gp. This protein functions as a pump to reduce the intracellular concentration of anticancer drugs. Clinical use of P-gp antagonists to inhibit drug efflux has been disappointing. Here we propose silencing the multidrug resistance MDR1 phenotype by retarding glycolipid metabolism via inhibition of glucosylceramide synthase GCS, a lipogenic enzyme associated with MDR1.We will determine whether inhibitors of GCS affect MDR1P-gp expression and chemotherapy sensitivity in drug-resistant breast cancer cells and determine whether GCS inhibitors forestall acquired resistance to chemotherapy in wild-type breast cancer cells. This is the first study to attack drug resistance in breast cancer by manipulating GCS and glycolipids, and as such, it represents a major shift in the research paradigm for drug resistance. This is also the first study to propose an approach that mighthave prophylactic as well as therapeutic value.