Purpose:Our previous study has shown that PTPRZ1-MET(ZM)fusion is a viable target for MET inhibitors in gliomas.However,the diversity and prevalence of somatic MET alterations in difuse gliomas are still elusive and n...Purpose:Our previous study has shown that PTPRZ1-MET(ZM)fusion is a viable target for MET inhibitors in gliomas.However,the diversity and prevalence of somatic MET alterations in difuse gliomas are still elusive and need to be extensively characterized for identifying novel therapeutic targets.Methods:Totally,1,350 glioma patients and 31 patient-derived cells were collected from the Chinese Glioma Genome Atlas(CGGA)and published data.All kinds of MET fusions and/or splicing variants(MET F/SVs)were identifed by bioinformatical methods.Single-cell RNA sequencing(scRNA-seq)were used for validation.In vitro experiments of drug resistance were conducted for the possibility of MET-targeted treatment.Results:MET F/SVs but not genomic amplifcation,were highly enriched in the secondary glioblastomas(sGBM)and marked worse prognosis.Further molecular and scRNA-seq analysis revealed that MET F/SVs were induced in the course of glioma evolution and highly associated with MET overexpression.Subsequent in vitro and the clinical study showed that cells and patients harboring MET F/SVs have better response to MET inhibitors.Conclusion:Our fndings expanded the percentage of gliomas with abnormal MET alterations and suggested that a subgroup of gliomas harboring MET F/SVs may beneft from MET-targeted therapy.展开更多
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 pot...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 in vitro and in vivo 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 ABCG2 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.展开更多
基金supported by grants from the Natural Science Foundation of China (NSFC)/Research Grants Council (RGC),Hong Kong,China Joint Research Scheme (81761168038)the National Natural Science Foundation of China (81802994,81903078,81972337,81972816,82002647,82192894,82103623,and 82002994)+3 种基金the Mainland-Hong Kong Joint Funding Scheme ITC grant MHP/004/19 and MOST grant 2019YFE0109400the Beijing Natural Science Foundation (JQ20030)Sino-German Center for Research Promotion (M-0020)the Beijing Nova Program (Z201100006820118).
文摘Purpose:Our previous study has shown that PTPRZ1-MET(ZM)fusion is a viable target for MET inhibitors in gliomas.However,the diversity and prevalence of somatic MET alterations in difuse gliomas are still elusive and need to be extensively characterized for identifying novel therapeutic targets.Methods:Totally,1,350 glioma patients and 31 patient-derived cells were collected from the Chinese Glioma Genome Atlas(CGGA)and published data.All kinds of MET fusions and/or splicing variants(MET F/SVs)were identifed by bioinformatical methods.Single-cell RNA sequencing(scRNA-seq)were used for validation.In vitro experiments of drug resistance were conducted for the possibility of MET-targeted treatment.Results:MET F/SVs but not genomic amplifcation,were highly enriched in the secondary glioblastomas(sGBM)and marked worse prognosis.Further molecular and scRNA-seq analysis revealed that MET F/SVs were induced in the course of glioma evolution and highly associated with MET overexpression.Subsequent in vitro and the clinical study showed that cells and patients harboring MET F/SVs have better response to MET inhibitors.Conclusion:Our fndings expanded the percentage of gliomas with abnormal MET alterations and suggested that a subgroup of gliomas harboring MET F/SVs may beneft from MET-targeted therapy.
基金supported by the Key Research and Development Program of Jiangsu Province (BE2020637,China)Wuxi double hundred young and middle-aged medical and health top-notch talent project (No.202014,China)。
文摘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 in vitro and in vivo 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 ABCG2 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.
