c-MET tyrosine kinase inhibitors reverse multidrug resistance in breast cancer cells by targeting ABCG2 transporter.

This article investigates the potential of c-MET receptor tyrosine kinase inhibitors (RTKIs)—specifically cabozantinib, crizotinib, and PHA-665752—to reverse multidrug resistance (MDR) mediated by the ATP-binding cassette transporter ABCG2 in breast cancer cells. Using mitoxantrone-resistant MCF-7/MX breast cancer cells, the study demonstrates that these c-MET RTKIs synergistically enhance the antiproliferative effects of mitoxantrone and increase intracellular accumulation of the drug by inhibiting ABCG2 efflux activity, an effect not observed in parental MCF-7 cells. Molecular docking and dynamics simulations further support that these inhibitors bind to the drug-binding domain of ABCG2, suggesting a mechanism for their reversal of MDR. The findings propose that c-MET RTKIs could be repurposed as effective agents to overcome ABCG2-associated drug resistance in cancer therapy when used in combination with conventional chemotherapeutics.