ABCG2/BCRP transporter-mediated Multidrug resistance (MDR) in cancers has been considered as one of the obstacles to the cancer chemotherapy. Our recent study characterized the MET inhibitor tepotinib as a potent ABCB1 inhibitor. In the present study, we demonstrated the MET inhibitor tepotinib effectively antagonized ABCG2-mediated MDR in vitro and in vivo. In addition, the ABCB1/ABCG2 double-transfected cell model demonstrated that tepotinib can simultaneously inhibit the two MDR transporters. Mechanistically, tepotinib stimulated ABCG2 ATPase activity without altering the protein expression level of ABCG2, MET, or p-MET. Moreover, the MDR reversal effect may be attributed to its reversible inhibition of ABCG2 substrate efflux function, thereby sensitizing the drug-resistant cancer cells to substrate drugs. The molecular docking analysis suggested that tepotinib may directly bind to the drug-binding site of ABCG2, which subsequently block the binding of ABCG2 substrates. Animal study showed that tepotinib significantly increased the intratumor accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect in ABCG2-overexpressing tumors. In conclusion, our study provides a new strategy of repositioning tepotinib as an MDR modulator to antagonize ABCG2-mediated MDR. Citation Format: Zhuoxun Wu, Qiu-Xu Teng, Yuqi Yang, Nikita Acharekar, Jing-Quan Wang, Min He, Sabesan Yoganathan, Jun Lin, Jian Wang, Zhe-Sheng Chen. Reversal of ABCG2-mediated multidrug resistance by tepotinib in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 409.
