Grant: Operating Grant

There are many drugs that can kill tumour cells, but all too frequently tumours develop ways of resisting these toxic agents. Thus, tumours are said to become "multidrug resistant". In 1992, we discovered a protein which we named Multidrug Resistance Protein, or MRP1. MRP1 makes tumour cells resistant to chemotherapy by pumping drugs out of cancer cells, and it is particularly important for limiting chemotherapy effectiveness in the childhood cancer neuroblastoma as well as certain adult solid tumours. MRP1 is also important because low amounts of this protein are found in normal cells where MRP1 can protect organs (eg testes, brain) by impeding entry of drugs and other foreign chemicals. Recently, MRP1 has also been found to play a role in protecting cells against oxidative stress. MRP1 is a particularly large membrane protein which makes it technically challenging to study. This project seeks to continue our internationally recognized program on MRP1 by addressing the following questions: (1) what determines how the MRP1 protein is efficiently synthesized and folded (and 'packed') into a transport-competent shape? (2) what features of MRP1's structure allow it to recognize so many drugs? (3) how do other proteins in the cell affect MRP1 activity and do any of them influence how much MRP1 is found on the cell surface where it determines the cell's capacity to pump out drugs? and (4) do naturally occurring genetic variants of MRP1 that are found individuals displaying different responses to drugs influence its activity and thus potentially influence a patient's responses to anti-cancer drugs as well as other drugs recognized by this protein? We believe the knowledge gained by our investigations will be greatly enhance our understanding of the role of MRP1 in determining drug response (and toxicity) in tumours as well as in normal tissues, and consequently, may ultimately help lead to more effective (and less toxic) chemotherapeutic interventions.