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

Area of Science:

• Pharmacology and Molecular Biology
• Cancer Therapeutics

Background:

• Sunitinib malate (Sutent) is a tyrosine kinase inhibitor (TKI) used for renal cell carcinoma and gastrointestinal stromal tumors.
• Some TKIs can overcome multidrug resistance (MDR) mediated by efflux pumps like P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2).
• Understanding TKI interactions with these transporters is crucial for optimizing cancer chemotherapy.

Purpose of the Study:

• To investigate the effects of sunitinib on P-gp and wild-type versus germ-line mutant BCRP.
• To determine if sunitinib can reverse MDR conferred by these transporters.
• To elucidate the role of specific BCRP residues in sunitinib's inhibitory activity.

Main Methods:

• Cell proliferation assays to assess drug resistance reversal.
• In vitro vesicle transport assays to measure transporter inhibition.
• Analysis of sunitinib interaction with wild-type and mutant BCRP variants (Q141K, R482G, R482S, F431L).

Main Results:

• Sunitinib significantly reversed BCRP-mediated MDR and partially reversed P-gp-mediated MDR.
• Sunitinib competitively inhibited BCRP-mediated estrone 3-sulfate and P-gp-mediated vincristine transport in vitro.
• The BCRP F431L variant, associated with the 1291T>C germ-line mutation, showed resistance to sunitinib and fumitremorgin C (FTC) inhibition, indicating Phe-431 is critical for interaction.

Conclusions:

• Sunitinib demonstrates activity against P-gp and BCRP drug efflux mechanisms.
• Germ-line variations in BCRP, such as F431L, can alter the drug's interaction and efficacy.
• These findings highlight the importance of BCRP genetic status in sunitinib's therapeutic effects and personalized chemotherapy strategies.