Date of Award


Document Type


Degree Name

Philosophy (Ph.D)


Pharmaceutical Sciences

First Advisor

Zhe-sheng Chen

Second Advisor

John Wurpel

Third Advisor

Sandra Reznik


Overexpression of ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 in cancer cells have been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Therefore, it is important to inhibit ABCB1/ABCG2 activity in order to maintain an effective intracellular level of chemotherapeutic drugs in drug-resistant cancer cells. Tepotinib is an ATP-competitive MET kinase inhibitor approved for the treatment of adult patients with metastatic non–small cell lung cancer harboring MET exon 14 skipping alterations. In the present study, we identified that the MET inhibitor tepotinib can reverse ABCB1- and ABCG2-mediated MDR by directly binding to the drug-binding site of the transporters and reversibly inhibiting drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and ABCG2 gene knockout cell model demonstrated that tepotinib specifically inhibits these two MDR-related ABC transporters. The ATPase assay showed that tepotinib concentration-dependently inhibited the ATPase activity of ABCB1 but stimulated the ATPase activity of ABCG2. Furthermore, treatment with tepotinib did not alter protein expression or subcellular localization of ABCB1/ABCG2. The docking simulation suggested a high binding affinity of tepotinib with ABCB1/ABCG2 drug-binding site. In mouse bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Taken together, our study provides a new potential of repositioning tepotinib as a dual ABCB1/ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize MDR.