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

Abstract

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 IC 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 IC 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.

A Proof-of-Concept Study to Inhibit ABCG2- and ABCB1-Mediated Efflux Transport at the Human Blood–Brain Barrier

“…Theoretically, erlotinib administration could have increased cerebral blood flow, which may have contributed to the observed increase in 11 C-erlotinib brain distribution. However, this possibility could not be assessed in our study because we did not measure cerebral blood flow (i.e., with 15 O-H 2 O). Unbound erlotinib plasma concentrations at the time of the PET scan ranged from 0.09 to 0.73 mmol/L, which was similar to or above the in vitro half-maximum inhibitory concentration of erlotinib for ABCG2 inhibition (0.13 mmol/L) and should therefore have led to substantial inhibition of ABCG2 transport activity at the BBB.…”

“…There is consequently an unmet need for a clinically available, marketed oral ABCB1/ABCG2 inhibitor. Numerous in vitro studies have investigated the potential of marketed tyrosine kinase inhibitors to overcome ABCB1/ABCG2mediated multidrug resistance of tumor cells (14)(15)(16). However, to date no clinical data are available to prove that ABCB1/ABCG2 inhibition can be achieved at the human BBB with these drugs.…”

Decreased expression of microRNA‑214 contributes to imatinib mesylate resistance of chronic myeloid leukemia patients by upregulating ABCB1 gene expression

“…IM resistance has become an important issue in the treatment of CML. Studies show that overexpression of multidrug transporter and drug target enzyme may be involved in IM resistance of CML (29–31). Multidrug transporters, such as PGP, MRPS, LRP and BCRP, can increase intracellular drug efflux or vesicle isolation, resulting in decreased intracellular drug concentration or altered drug distribution.…”

PharmGKB summary

“…Pazopanib is a substrate for efflux transporters ABCB1 (also known as PgP and MDR1) and ABCG2 (also called BCRP)[13–15]. Studies in transfected cell lines suggest that pazopanib is a weak substrate for ABCB1 and a stronger substrate for ABCG2 but both were equally important for transport at the blood-brain barrier in a mouse model study [15].…”

“…Studies in transfected cell lines suggest that pazopanib is a weak substrate for ABCB1 and a stronger substrate for ABCG2 but both were equally important for transport at the blood-brain barrier in a mouse model study [15]. Several TKIs are able to act as both substrate and inhibitors for ABCB1 and ABCG2, and in vitro studies indicate that pazopanib is a strong inhibitor of both transporters [13]. The pazopanib drug label also indicates that it is an inhibitor of ABCB1.…”