Ronilda D'Cunha, SoHyun Bae, Daryl J. Murry, Guohua An

The overexpression of efflux transporters, especially P-glycoprotein (Pgp, MDR1, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2), represents an important mechanism of multidrug resistance (MDR). Tyrosine kinase inhibitors (TKIs), a novel group of target-specific anticancer drugs, have recently been found to interact with Pgp and BCRP and serve as both substrates and inhibitors. Considering their dual role, we anticipate that combination TKI therapy may represent a promising strategy to reverse efflux transporter mediated TKI resistance. Presently, investigations on these interactions are very limited. To fill in the literature gap, we used dasatinib as the model drug and evaluated the effect of various TKIs on Pgp- and BCRP- mediated dasatinib efflux. Cell uptake studies were performed using LLC-PK1 and MDCK-II cells along with their sub clones that were transfected with human Pgp and BCRP, respectively. Among the 14 TKIs screened, 9 TKIs greatly inhibited Pgp- mediated dasatinib efflux at 50 μM. Further concentration dependent studies showed that imatinib, nilotinib and pazopanib were potent Pgp inhibitors with IC50 values of 2.42, 6.11 and 8.06 μM, respectively. Additionally, 50 μM of 5 TKIs greatly increased dasatinib accumulation through BCRP inhibition. Concentration dependent studies revealed that imatinib, erlotinib, nilotinib, axitinib and pazopanib were potent BCRP inhibitors with IC50 values of 0.94, 2.23, 2.50, 6.89 and 10.4 μM, respectively. Our findings point to potential combinations of TKIs that could enhance intracellular concentrations of the targeted TKI, overcome MDR and improve TKI efficacy. Further in vivo studies are warranted to confirm the efflux transporter-mediated TKI-TKI interaction.