The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in v...The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in various types of cancers at low rates.In the last few years,two potent and selective RET protein tyrosine kinase inhibitors(TKIs),pralsetinib(BLU-667)and selpercatinib(LOXO-292,LY3527723)were developed and received regulatory approval.Although pralsetinib and selpercatinib gave high overall response rates(ORRs),<10%of patients achieved a complete response(CR).The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations,acquired alternative oncogenes,or MET amplification.RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib.Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials.However,it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs.Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.展开更多
肺癌是世界上最大的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)占肺癌的80%.肺癌发病快,死亡率高,严重威胁人类健康.普拉替尼(Pralsetinib)是一种选择性转染重排(rearranged during transfection,RET)抑制剂,用于转移性RET融合阳性NSCLC患...肺癌是世界上最大的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)占肺癌的80%.肺癌发病快,死亡率高,严重威胁人类健康.普拉替尼(Pralsetinib)是一种选择性转染重排(rearranged during transfection,RET)抑制剂,用于转移性RET融合阳性NSCLC患者的治疗.本文就Pralsetinib的合成、药效学、药代动力学以及毒副作用等几个方面对Pralsetinib进行介绍.展开更多
目的通过对抗肿瘤创新药普拉替尼药物不良反应(adverse drug reactions,ADR)信号的挖掘分析,为临床安全用药提供参考。方法基于海南省药品ADR监测中心2020年9月—2021年7月数据,运用ROR法和MHRA法挖掘普拉替尼ADR风险信号。结果根据监...目的通过对抗肿瘤创新药普拉替尼药物不良反应(adverse drug reactions,ADR)信号的挖掘分析,为临床安全用药提供参考。方法基于海南省药品ADR监测中心2020年9月—2021年7月数据,运用ROR法和MHRA法挖掘普拉替尼ADR风险信号。结果根据监管活动医学词典的系统器官分类,普拉替尼ADR损害主要集中在各类检查指标(39.6%),血液及淋巴系统疾病(20.8%),肝胆系统疾病(14.6%)。采用ROR法、MHRA法挖掘到普拉替尼ADR 5个风险信号:中性粒细胞计数减少,骨髓抑制,肝功能异常,丙氨酸氨基转移酶升高,天门冬氨酸氨基转移酶升高;还存在一些可疑信号,特别是说明书未提及的潜在ADR信号,如肾功能损害,急性心肌梗死,在临床用药过程中仍需警惕。结论采用ROR法、MHRA法有效挖掘出普拉替尼的ADR风险信号,临床用药时应关注普拉替尼导致的各种ADR,为临床安全用药提供参考。展开更多
基金Cancer research in Jie Wu’s laboratory was supported by NIH grants R01CA242845,R01CA273168,a PHF SEED grantOklahoma Center for the Advancement of Science and Technology(OCAST)grant HR19-026Additional support was provided by the Oklahoma Tobacco Settlement Endowment Trust,and the Peggy and Charles Stephenson Endowment,and NIH grants P30CA225520 and P20GM103639 to the institution.
文摘The rearranged during transfection(RET)is a receptor protein tyrosine kinase.Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer(NSCLC)and in thyroid cancer,but also increasingly in various types of cancers at low rates.In the last few years,two potent and selective RET protein tyrosine kinase inhibitors(TKIs),pralsetinib(BLU-667)and selpercatinib(LOXO-292,LY3527723)were developed and received regulatory approval.Although pralsetinib and selpercatinib gave high overall response rates(ORRs),<10%of patients achieved a complete response(CR).The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations,acquired alternative oncogenes,or MET amplification.RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib.Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials.However,it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs.Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors.
文摘肺癌是世界上最大的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)占肺癌的80%.肺癌发病快,死亡率高,严重威胁人类健康.普拉替尼(Pralsetinib)是一种选择性转染重排(rearranged during transfection,RET)抑制剂,用于转移性RET融合阳性NSCLC患者的治疗.本文就Pralsetinib的合成、药效学、药代动力学以及毒副作用等几个方面对Pralsetinib进行介绍.
文摘目的通过对抗肿瘤创新药普拉替尼药物不良反应(adverse drug reactions,ADR)信号的挖掘分析,为临床安全用药提供参考。方法基于海南省药品ADR监测中心2020年9月—2021年7月数据,运用ROR法和MHRA法挖掘普拉替尼ADR风险信号。结果根据监管活动医学词典的系统器官分类,普拉替尼ADR损害主要集中在各类检查指标(39.6%),血液及淋巴系统疾病(20.8%),肝胆系统疾病(14.6%)。采用ROR法、MHRA法挖掘到普拉替尼ADR 5个风险信号:中性粒细胞计数减少,骨髓抑制,肝功能异常,丙氨酸氨基转移酶升高,天门冬氨酸氨基转移酶升高;还存在一些可疑信号,特别是说明书未提及的潜在ADR信号,如肾功能损害,急性心肌梗死,在临床用药过程中仍需警惕。结论采用ROR法、MHRA法有效挖掘出普拉替尼的ADR风险信号,临床用药时应关注普拉替尼导致的各种ADR,为临床安全用药提供参考。
