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

Haruka Kawahara, Kohji Noguchi, Kazuhiro Katayama, Junko Mitsuhashi, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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).

Original languageEnglish
Pages (from-to)1493-1500
Number of pages8
JournalCancer Science
Volume101
Issue number6
DOIs
Publication statusPublished - 2010 Jun

Fingerprint

Germ-Line Mutation
Pharmacology
Breast Neoplasms
Proteins
P-Glycoprotein
Germ Cells
sunitinib
ATP Binding Cassette Transporter, Sub-Family G, Member 2
Transport Vesicles
Gastrointestinal Stromal Tumors
ATP-Binding Cassette Transporters
Multiple Drug Resistance
Vincristine
Renal Cell Carcinoma
Drug Resistance
Protein-Tyrosine Kinases
Alleles
Cell Proliferation
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Pharmacological interaction with sunitinib is abolished by a germ-line mutation (1291T>C) of BCRP/ABCG2 gene. / Kawahara, Haruka; Noguchi, Kohji; Katayama, Kazuhiro; Mitsuhashi, Junko; Sugimoto, Yoshikazu.

In: Cancer Science, Vol. 101, No. 6, 06.2010, p. 1493-1500.

Research output: Contribution to journalArticle

Kawahara, Haruka ; Noguchi, Kohji ; Katayama, Kazuhiro ; Mitsuhashi, Junko ; Sugimoto, Yoshikazu. / Pharmacological interaction with sunitinib is abolished by a germ-line mutation (1291T>C) of BCRP/ABCG2 gene. In: Cancer Science. 2010 ; Vol. 101, No. 6. pp. 1493-1500.
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