Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

Sunitinib malate (Sutent, SU11248) is a small‐molecule multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and imatinib‐resistant gastrointestinal stromal tumors. Some TKIs can overcome multidrug resistance conferred by ATP‐binding cassette transporter, P‐glycoprotein (P‐gp)/ABCB1, multidrug resistance‐associated protein 1 (MRP1)/ABCC1, and breast cancer resistance protein (BCRP)/ABCG2. Here, we analyzed the effects of sunitinib on P‐gp and on wild‐type and germ‐line mutant BCRPs. Sunitinib remarkably reversed BCRP‐mediated and partially reversed P‐gp‐mediated drug resistance in the respective transfectants. The in vitro vesicle transport assay indicated that sunitinib competitively inhibited BCRP‐mediated estrone 3‐sulfate transport and P‐gp‐mediated vincristine transport. These inhibitory effects of sunitinib were further analyzed in Q141K‐, R482G‐, R482S‐, and F431L‐variant BCRPs. Intriguingly, the F431L‐variant BCRP, which is expressed by a germ‐line mutant allele 1291T>C, was almost insensitive to both sunitinib‐ and fumitremorgin C (FTC)‐mediated inhibition in a cell proliferation assay. Sunitinib and FTC did not inhibit ¹²⁵I‐iodoarylazidoprazosin‐binding to F431L‐BCRP. Thus, residue Phe‐431 of BCRP is important for the pharmacological interaction with sunitinib and FTC. Collectively, this is the first report showing a differential effect of a germ‐line variation of the BCRP/ABCG2 gene on the pharmacological interaction between small‐molecule TKIs and BCRP. These findings would be useful for improving our understanding of the pharmaceutical effects of sunitinib in personalized chemotherapy. (Cancer Sci 2010; 00: 000–000)