Golvatinib (E7050) restores chemosensitivity in multidrug-resistant cancer cells by inhibiting ABCG2 transporter.

ABCG2-mediated drug efflux is a major cause of multidrug resistance (MDR), reducing the activity of various anticancer agents. This study evaluated the role of Golvatinib, originally developed as a c-MET/VEGFR2 inhibitor, as a potential ABCG2 modulator in ABCG2-expressing MDR cells. Golvatinib significantly restored cellular sensitivity to representative ABCG2 substrates, by inhibiting efflux of substrates and increasing intracellular drug accumulation. ABCG2 expression and membrane localization remained unchanged, indicating that this reversal was not due to downregulation or relocation of ABCG2 transporter. Cellular thermal shift analysis supported direct engagement of Golvatinib with the ABCG2 transporter, and apoptosis assay showed that the combination restored chemotherapy-induced cell death in MDR cancer cells. In addition, chemosensitization remained significant in 3D spheroid cell culture. Molecular docking with ABCG2 predicted that Golvatinib binds within the transmembrane drug-binding pocket, consistent with competitive/steric inhibition of substrate transport. These results support the rationale of Golvatinib as a candidate for combination therapy strategies targeting ABCG2-related MDR.