Chemotherapy drug resistance is a major obstacle in the treatment of cancer. It can result from an increase in levels of cellular drug efflux pumps such as P-glycoprotein (P-gp). Using cellular models, this thesis aimed to investigate resistance in lung cancer cells while developing siRNA and membrane proteomic techniques and to increase our knowledge of the effect of lapatinib, a newly developed targeted therapy, in these resistant cells.
Lapatinib, a growth factor receptor tyrosine kinase inhibitor synergised with P-gp substrate cytotoxics in P-gp over-expressing resistant cells. However, lapatinib treatment, at clinically relevant concentrations, also increased levels of the P-gp drug transporter in a dose-responsive manner. Conversely, exposure to the epidermal growth factor (EGF), an endogenous growth factor receptor ligand, resulted in a decrease in P-gp expression. Using drug accumulation, efflux and toxicity assays we determined that alteration in P-gp levels by either lapa...