Uptake/ efflux molecular mechanisms responsible for bosutinib multidrug resistance

The multidrug resistance (MDR) has been identified in the 70s as a major cause of resistance to treatment with several unrelated agents. In the following 40 years MDR has been characterized in dept, and the molecular causes at the basis of this drug resistance are now largely known. The drug transporters play a central role in MDR, as the alteration of their expression levels is strictly related with MDR development. Down-regulation of uptake drug transporters and/or up-regulation of efflux drug transporters correlate with lower intracellular drug concentration, reduced activity on the target, and with resistance to treatment. The tyrosine kinase inhibitor (TKI) imatinib, currently the first line therapy for chronic myeloid leukemia (CML), showed MDR in presence of altered expression levels of OCT-1 (in patients), P-gp and BCRP (in vitro). The possible indication of OCT-1 levels as a prognostic factor for imatinib treatment is currently under debate. The hypothesis would be to increase the daily dose in patients with low expression levels of OCT-1. The emerging therapeutic options for CML, mainly represented by new tyrosine kinase inhibitors nilotinib, dasatinib and bosutinib, offer a valid alternative in presence of imatinib MDR. Indeed, nilotinib and dasatinib show a different uptake/efflux pattern compared to imatinib, and it could be hypothesized that their efficacy could be unaffected by the drug transporters expression levels. The identification of drug transporters involved in new tyrosine kinase inhibitors is actually an active research field. My PhD project focused on the identification of uptake/efflux mechanisms for a new TKI, bosutinib. First I produced cell lines overexpressing and overexpressing plus silencing the three main drug transporter. Then I evaluated the reliability of the cell models. Then I identified which transporter could be involved in bosutinib uptake/efflux, and finally I studied the biological and molecular relevance of the interaction between bosutinib and drug transporters.