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

Cancer Sci. 2010 Jun;101(6):1493-500. doi: 10.1111/j.1349-7006.2010.01539.x. Epub 2010 Feb 22.


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 (125)I-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / physiology
  • Animals
  • Azides / metabolism
  • Drug Resistance, Neoplasm
  • Estrone / analogs & derivatives
  • Estrone / pharmacokinetics
  • Germ-Line Mutation*
  • Humans
  • Indoles / pharmacology*
  • K562 Cells
  • Mice
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / physiology
  • Prazosin / analogs & derivatives
  • Prazosin / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrroles / pharmacology*
  • Sunitinib
  • Vincristine / pharmacokinetics


  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Azides
  • Indoles
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Pyrroles
  • Estrone
  • Vincristine
  • azidoprazosin
  • estrone sulfate
  • Sunitinib
  • Prazosin