LAUSR

Graphical abstract Figure. No Caption available. ABSTRACT Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c‐Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP‐binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug‐selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2‐482‐R2, ABCG2‐482‐G2, and ABCG2‐482‐T7, which overexpress ABCG2. Cabozantinib, at non‐toxic concentrations (3 or 5 &mgr;M), sensitized the ABCG2‐overexpressing cells to mitoxantrone, SN‐38, and topotecan. Our results indicate that cabozantinib reverses ABCG2‐mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug‐binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.