TKI combination therapy: strategy to enhance dasatinib uptake by inhibiting Pgp- and BCRP-mediated efflux

Biopharm Drug Dispos. 2016 Oct;37(7):397-408. doi: 10.1002/bdd.2022. Epub 2016 Sep 13.


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 to 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 the literature gap, dasatinib was used as the model drug and the effects of various TKIs on Pgp- and BCRP- mediated dasatinib efflux were evaluated. Cell uptake studies were performed using LLC-PK1 and MDCK-II cells along with their subclones that were transfected with human Pgp and BCRP, respectively. Among the 14 TKIs screened, nine 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 five 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. Copyright © 2016 John Wiley & Sons, Ltd.

Keywords: P-glycoprotein (Pgp); breast cancer resistance protein (BCRP); tyrosine kinase inhibitors (TKI).

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biological Transport
  • Dasatinib / pharmacology*
  • Dogs
  • Drug Interactions
  • Drug Resistance, Multiple
  • LLC-PK1 Cells
  • Madin Darby Canine Kidney Cells
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Swine


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Dasatinib