PXR-mediated P-glycoprotein induction by small molecule tyrosine kinase inhibitors

The rapid development of drug resistance as a result of exposure to small molecule tyrosine kinase inhibitors (TKIs) is an important drawback to the successful use of these agents in the clinic. Although one of the most established mechanisms by which cells acquire drug resistance to anticancer drugs is the up regulation of drug efflux transporters such as P-glycoprotein (PGP), it is currently still unknown whether TKIs have the propensity to induce PGP. The effect of TKIs on the protein expression and activity of PGP was assessed after treatment of LS180 cells with clinically relevant concentrations of the TKIs. In addition, the involvement of the nuclear pregnane X receptor (PXR), a known regulator of PGP expression, was determined. At least five out of the nine tested TKIs (erlotinib, gefitinib, nilotinib, sorafenib, vandetanib) were able to induce the expression of PGP within 48 h in LS180 cells. Accordingly, these TKIs were also shown to affect the accumulation of a P-glycoprotein specific probe substrate. Furthermore, we showed that the pregnane X receptor (PXR), which is an important regulator of PGP induction, is involved in the upregulation of PGP protein expression following exposure to these TKIs. Our data show that PXR-mediated upregulation of PGP expression by TKIs might be a possible mechanism underlying acquired drug resistance in cancer cells.

In this paper, we demonstrate that pregnane X receptor (PXR)-mediated induction of P-glycoprotein (PGP) is an important mechanism by which tyrosine kinase inhibitors (TKI; red square) can affect the uptake of PGP substrates (purple squares). PGP, the product of multidrug resistance (MDR)-1, is a broad-spectrum drug efflux transporter protein. Since many anticancer drugs (including TKIs) are substrates of PGP, induction of PGP causes the active extrusion of these agents before exerting their pharmacologic effects on their intracellular targets, thus rendering the cell resistant to these agents.Figure optionsDownload high-quality image (118 K)Download as PowerPoint slide