1文献来源Paik PK,Felip E,Veillon R,et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations[J]. N Engl J Med,2020,383(10):931-943.2证据水平2b。3背景约3%~4%非小细胞肺癌(non-small-cell lung can...1文献来源Paik PK,Felip E,Veillon R,et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations[J]. N Engl J Med,2020,383(10):931-943.2证据水平2b。3背景约3%~4%非小细胞肺癌(non-small-cell lung cancer,NSCLC)患者具有MET 14外显子跳读突变。Tepotinib是高选择性口服MET抑制剂,既往研究表明,tepotinib在MET驱动的肿瘤患者中已显示出令人鼓舞的临床活性。展开更多
Tepotinib is a key drug for cancer patients with mesenchymal-epithelial transition receptor tyrosine kinase proto-oncogene(MET)exon 14 skipping mutation.However,its bioavailability in the cerebrospinal fluid(CSF)in hu...Tepotinib is a key drug for cancer patients with mesenchymal-epithelial transition receptor tyrosine kinase proto-oncogene(MET)exon 14 skipping mutation.However,its bioavailability in the cerebrospinal fluid(CSF)in humans has not been fully elucidated.Moreover,information about the efficacy of tepotinib in patients with leptomeningeal metastasis is limited.Here,we present the case of a 56-year-old man who was diagnosed with lung adenocarcinoma with MET exon 14 skipping mutation.He was urgently hospitalized due to leptomeningeal metastasis.We administered tepotinib 500 mg/day as the second-line therapy and observed improvement in leptomeningeal metastasis and performance status.The tepotinib concentrations reached 1,648 ng/mL in the plasma and 30.6 ng/mL in the CSF,with a penetration rate(CSF/plasma)of 1.83%.These demonstrate tepotinib could achieve a high rate of central nervous system transition and could be effective against leptomeningeal metastasis.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
文摘1文献来源Paik PK,Felip E,Veillon R,et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations[J]. N Engl J Med,2020,383(10):931-943.2证据水平2b。3背景约3%~4%非小细胞肺癌(non-small-cell lung cancer,NSCLC)患者具有MET 14外显子跳读突变。Tepotinib是高选择性口服MET抑制剂,既往研究表明,tepotinib在MET驱动的肿瘤患者中已显示出令人鼓舞的临床活性。
文摘Tepotinib is a key drug for cancer patients with mesenchymal-epithelial transition receptor tyrosine kinase proto-oncogene(MET)exon 14 skipping mutation.However,its bioavailability in the cerebrospinal fluid(CSF)in humans has not been fully elucidated.Moreover,information about the efficacy of tepotinib in patients with leptomeningeal metastasis is limited.Here,we present the case of a 56-year-old man who was diagnosed with lung adenocarcinoma with MET exon 14 skipping mutation.He was urgently hospitalized due to leptomeningeal metastasis.We administered tepotinib 500 mg/day as the second-line therapy and observed improvement in leptomeningeal metastasis and performance status.The tepotinib concentrations reached 1,648 ng/mL in the plasma and 30.6 ng/mL in the CSF,with a penetration rate(CSF/plasma)of 1.83%.These demonstrate tepotinib could achieve a high rate of central nervous system transition and could be effective against leptomeningeal metastasis.
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.
