Imatinib-induced upregulation of ABCG2 (BCRP) and ABCB1 (MDR1) may represent a novel mechanism of pharmacokinetic drug resistance in cancer patients chronically treated with imatinib

Abstract

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Imatinib mesylate (Gleevec) shows selective inhibition of the tyrosine kinase activity of the BCR-ABL fusion protein and of the receptors for the stem cell factor (c-KIT) and platelet-derived growth factor. This archetype of a targeted drug is successfully used in the treatment of Ph+ chronic and acute leukemias, and gastrointestinal stromal tumors. Since imatinib is taken orally on a daily basis, it is conceivable that this chronic administration may eventually lead to development of cellular resistance and subsequent treatment failure. Indeed, the vast majority of patients progress while on therapy and several imatinib resistance mechanisms have been documented. Gene amplification or somatic mutations in the drug’s target genes are generally thought to be responsible for this acquired unresponsiveness. We investigated whether ABC drug pumps are also implicated in imatinib resistance. First we examined whether imatinib is a substrate for the ABCG2 drug pump. Using a panel of well-defined ABCG2-overexpressing cell lines we demonstrated that imatinib is indeed a substrate for ABCG2, that it competes with mitoxantrone for drug export, and that ABCG2-mediated efflux can be reversed by the fumitremorgin C analog Ko-143. Furthermore, ABCB1-mediated outward transport of imatinib was demonstrated in drug uptake experiments using C¹⁴ labeled imatinib, in line with previous reports. Evidently, imatinib is a substrate for both ABCG2 and ABCB1. Since both drug pumps are highly expressed in the gastrointestinal tract, they might not only play a role in cellular resistance of tumor cells but also influence the gastrointestinal absorption of imatinib. So next, we investigated whether chronic oral administration of imatinib might lead to the induction of intestinal transport proteins such as ABCB1, ABCG2, ABCC1 and ABCC2 (MRP1/2). Using Caco-2 cells as an in vitro model for intestinal drug transport, we found that continuous exposure to imatinib (10 μM) specifically upregulates the expression of ABCG2 and ABCB1. The drug-induced gene activation was not mediated by the human orphan nuclear receptor SXR. Importantly, long-term exposure of Caco-2 cells to imatinib resulted in a decreased intracellular accumulation (∼50%) due to enhanced ABCG2- and ABCB1-mediated efflux. It might be anticipated that drug-induced upregulation of these intestinal pumps reduce the oral bioavailability of imatinib, and thereby represent a mechanism of acquired pharmacokinetic drug resistance in cancer patients chronically treated with imatinib. So, our own in vitro findings and several in vivo observations provide evidence that pharmacokinetic resistance may also play a definitive role in the ultimate resistance of patients on chronic imatinib. The latter may have serious implications for the chronic imatinib treatment of cancer patients.