Overcoming drug efflux pumps to restore sensitivity to anti-cancer drugs
Chemotherapy is used in oncology as a front-line therapy, as an adjuvant to surgery/radiotherapy and even in palliative care. However, despite initial reduction in tumour size, the vast majority of cancers become unresponsive to chemotherapy. The reason for this failure is the inherent or acquired resistance phenotype. Drug resistance in cancer is caused by numerous cell based or tissue factors. One of the most prevalent mechanisms involves the over-expression of drug efflux pumps. These proteins confer resistance by preventing sufficient accumulation of anti-cancer drugs inside cells.
The ABC transporter P-glycoprotein (P-gp)is expressed in a wide variety of resistant cancers and is associated with poor patient outcome. A characteristic feature of P-gp is its ability to interact with over 200 known drugs. Unfortunately, the mechanistic understanding of this "multidrug recognition" remains an enigma. The research project will attempt to locate and characterise the drug binding site(s) on P-gp. By understanding how this enigmatic protein interacts with drugs it will be possible to design inhibitors and thereby restore the effectiveness of chemotherapy in cancer.