Abstract
Overexpression of ABCB1 (also called P-glycoprotein) confers resistance to multiple anticancer drugs, including tyrosine kinase inhibitors (TKIs). Several ABCB1 single nucleotide polymorphisms affect the transporter activity. The most common ABCB1 variants are 1236C > T, 2677G > T, 3435C > T and have been associated with clinical response to imatinib in chronic myelogenous leukaemia (CML) in some studies. We evaluated the impact of these polymorphisms on the anti-proliferative effect and the intracellular accumulation of TKIs (imatinib, nilotinib, dasatinib and ponatinib) in transfected HEK293 and K562 cells. ABCB1 overexpression increased the resistance of cells to doxorubicin, vinblastine and TKIs. Imatinib anti-proliferative effect and accumulation were decreased to a larger extent in cells expressing the ABCB1 wild-type protein compared with the 1236T-2677T-3435T variant relatively to control cells. By contrast, ABCB1 polymorphisms influenced the activity of nilotinib, dasatinib and ponatinib to a much lesser extent. In conclusion, our data suggest that wild-type ABCB1 exports imatinib more efficiently than the 1236T-2677T-3435T variant protein, providing a molecular basis for the reported association between ABCB1 polymorphisms and the response to imatinib in CML. Our results also point to a weaker impact of ABCB1 polymorphisms on the activity of nilotinib, dasatinib and ponatinib.
Highlights
Overexpression of ABCB1 confers resistance to multiple anticancer drugs, including tyrosine kinase inhibitors (TKIs)
Similar ABCB1 surface expression was ensured by sorting recombinant cells by fluorescence activated cell sorting (FACS) with fluorescence parameters gated on the same level of intensity
Since ABCB1 has been reported to transport Tyrosine kinase inhibitors (TKIs), we investigated the impact of ABCB1 variant expression on K562 cell proliferation in the presence of TKIs that target BCR-ABL namely imatinib, nilotinib, dasatinib and ponatinib
Summary
Overexpression of ABCB1 ( called P-glycoprotein) confers resistance to multiple anticancer drugs, including tyrosine kinase inhibitors (TKIs). We have focused on clinically approved TKIs targeting BCR-ABL, a fusion protein which results from the reciprocal translocation between BCR (breakpoint cluster region) on chromosome 22 and ABL1 (Abelson kinase) on chromosome 91 These drugs, namely, imatinib, nilotinib, dasatinib and ponatinib have spectacularly improved the survival of patients with chronic myeloid leukaemia (CML)[2,3,4,5]. As a complement to population studies, recombinant cell lines are very useful to test the functional impact of genetic variants Along this idea, two studies have analysed the TKIs transport activity of ABCB1 in transfected cultured cells. HEK293 is a commonly used model to test ABC transporter variants whereas K562 is derived from a human myeloid leukaemia carrying the BCR-ABL1 fusion and is suitable for testing the activity of TKIs. In this report, we have evaluated the influence of these SNPs on ABCB1 activity towards imatinib. Little information is available regarding the impact of ABCB1 polymorphisms on these three drugs
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