Wu Zhuo-Xun, Teng Qiu-Xu, Yang Yuqi, Acharekar Nikita, Wang Jing-Quan, He Min, Yoganathan Sabesan, Lin Jun, Wang Jian, Chen Zhe-Sheng
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Department of Radiotherapy, the Affiliated Jiangyin People's Hospital of Nantong University, Jiangyin 214400, China.
Acta Pharm Sin B. 2022 May;12(5):2609-2618. doi: 10.1016/j.apsb.2021.12.018. Epub 2021 Dec 30.
Overexpression of ABCG2 transporter in cancer cells has been linked to the development of multidrug resistance (MDR), an obstacle to cancer therapy. Our recent study uncovered that the MET inhibitor, tepotinib, is a potent reversal agent for ABCB1-mediated MDR. In the present study, we reported for the first time that the MET inhibitor tepotinib can also reverse ABCG2-mediated MDR and by directly binding to the drug-binding site of ABCG2 and reversibly inhibiting ABCG2 drug efflux activity, therefore enhancing the cytotoxicity of substrate drugs in drug-resistant cancer cells. Furthermore, the ABCB1/ABCG2 double-transfected cell model and gene knockout cell model demonstrated that tepotinib specifically inhibits the two MDR transporters. In mice bearing drug-resistant tumors, tepotinib increased the intratumoral accumulation of ABCG2 substrate drug topotecan and enhanced its antitumor effect. Therefore, our study provides a new potential of repositioning tepotinib as an ABCG2 inhibitor and combining tepotinib with substrate drugs to antagonize ABCG2-mediated MDR.
癌细胞中ABCG2转运蛋白的过表达与多药耐药性（MDR）的产生有关，这是癌症治疗的一个障碍。我们最近的研究发现，MET抑制剂替泊替尼是ABCB1介导的多药耐药性的有效逆转剂。在本研究中，我们首次报道MET抑制剂替泊替尼还可以逆转ABCG2介导的多药耐药性，它通过直接结合ABCG2的药物结合位点并可逆地抑制ABCG2的药物外排活性，从而增强底物药物在耐药癌细胞中的细胞毒性。此外，ABCB1/ABCG2双转染细胞模型和基因敲除细胞模型表明，替泊替尼特异性抑制这两种多药耐药转运蛋白。在携带耐药肿瘤的小鼠中，替泊替尼增加了ABCG2底物药物拓扑替康在肿瘤内的蓄积，并增强了其抗肿瘤作用。因此，我们的研究为将替泊替尼重新定位为ABCG2抑制剂以及将替泊替尼与底物药物联合使用以对抗ABCG2介导的多药耐药性提供了新的可能性。
