Mutated and activated RAS is a key oncogene that drives various human cancers.RAS-targeted therapy has been an extensive research focus but has made little progress given its long history.Several novel binding sites,e...Mutated and activated RAS is a key oncogene that drives various human cancers.RAS-targeted therapy has been an extensive research focus but has made little progress given its long history.Several novel binding sites,especially the Cys12 mutation in KRAS G12C,have been identified,paving the way for irreversible inhibitor development.A series of clinical trials have proven their efficacies,and the first RAS G12C-targeting drug sotorasib(AMG-510)received approval for non-small cell lung cancer treatment in May,2021.In another approach,the development of indirect RAS inhibitors that target components of the RAS signaling pathway,including the upstream enzyme farnesyl transferase and the downstream effector molecules SOS1,MEK,AKT,and SHP2,has also made significant progress.This review systematically summarizes the latest progress in RAS signaling pathway-targeted drugs,discusses clinical challenges,and proposes beneficial strategies for RAStargeted therapy.展开更多
Consecutively hospitalized patients with confirmed coronavirus disease 2019(COVID-19)in Wuhan,China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin...Consecutively hospitalized patients with confirmed coronavirus disease 2019(COVID-19)in Wuhan,China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin–angiotensin system inhibitor(RAS-I)and the outcome of this disease.Associations between the use of RAS-I(angiotensin-converting enzyme inhibitor(ACEI)or angiotensin receptor blocker(ARB)),ACEI,and ARB and in-hospital mortality were analyzed using multivariate Cox proportional hazards regression models in overall and subgroup of hypertension status.A total of 2771 patients with COVID-19 were included,with moderate and severe cases accounting for 45.0%and 36.5%,respectively.A total of 195(7.0%)patients died.RAS-I(hazard ratio(HR)=0.499,95%confidence interval(CI)0.325–0.767)and ARB(HR=0.410,95%CI 0.240–0.700)use was associated with a reduced risk of all-cause mortality among patients with COVID-19.For patients with hypertension,RAS-I and ARB applications were also associated with a reduced risk of mortality with HR of 0.352(95%CI 0.162–0.764)and 0.279(95%CI 0.115–0.677),respectively.RAS-I exhibited protective effects on the survival outcome of COVID-19.ARB use was associated with a reduced risk of all-cause mortality among patients with COVID-19.展开更多
基金the National Natural Science Foundation of China(No.82173662,81772590 and 81572395)the Natural Science Foundation of Shanghai(No.20ZR1410400)the Extraordinary 2025 Elite Project of Fudan University,the Open Funding of Key Laboratory of Diagnosis and Treatment of Severe Hepato-pancreatic Diseases of Zhejiang Province,and the CAS Interdisciplinary Innovation Team JCTD-2019-07.
文摘Mutated and activated RAS is a key oncogene that drives various human cancers.RAS-targeted therapy has been an extensive research focus but has made little progress given its long history.Several novel binding sites,especially the Cys12 mutation in KRAS G12C,have been identified,paving the way for irreversible inhibitor development.A series of clinical trials have proven their efficacies,and the first RAS G12C-targeting drug sotorasib(AMG-510)received approval for non-small cell lung cancer treatment in May,2021.In another approach,the development of indirect RAS inhibitors that target components of the RAS signaling pathway,including the upstream enzyme farnesyl transferase and the downstream effector molecules SOS1,MEK,AKT,and SHP2,has also made significant progress.This review systematically summarizes the latest progress in RAS signaling pathway-targeted drugs,discusses clinical challenges,and proposes beneficial strategies for RAStargeted therapy.
基金supported by grants from Special Research Fund of PKU for Prevention and Control of COVID-19 and the Fundamental Research Funds for the Central Universities(Nos.PKU2020P-KYZX003,BMU2020HKYZX007)the National Natural Science Foundation of China(Nos.91846101,81771938,81301296,81900665,81570667,81470948,81670633)+8 种基金Major Research Plan of the National Natural Science Foundation of China(No.91742204)The International(Regional)Cooperation and Exchange Projects(NSFC-DFG,No.81761138041)Beijing Nova Programme Interdisciplinary Cooperation Project(No.Z1911-00001119008)the National Key R&D Program of the Ministry of Science and Technology of China(Nos.2016YFC1305405,2019-YFC2005000,2018YFC1314003-1,,2015BAI12B07)National Key Research and Development Program(No.2016YFC0906103)the University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research(Nos.BMU20160466,BMU2018JI012,BMU2019JI005)Beijing Advanced Discipline Construction Project(No.BMU-2019GJJXK001)PKU-Baidu Fund(No.2019BD017)from Peking University(Nos.BMU2018MX020,PKU2017LCX05).
文摘Consecutively hospitalized patients with confirmed coronavirus disease 2019(COVID-19)in Wuhan,China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin–angiotensin system inhibitor(RAS-I)and the outcome of this disease.Associations between the use of RAS-I(angiotensin-converting enzyme inhibitor(ACEI)or angiotensin receptor blocker(ARB)),ACEI,and ARB and in-hospital mortality were analyzed using multivariate Cox proportional hazards regression models in overall and subgroup of hypertension status.A total of 2771 patients with COVID-19 were included,with moderate and severe cases accounting for 45.0%and 36.5%,respectively.A total of 195(7.0%)patients died.RAS-I(hazard ratio(HR)=0.499,95%confidence interval(CI)0.325–0.767)and ARB(HR=0.410,95%CI 0.240–0.700)use was associated with a reduced risk of all-cause mortality among patients with COVID-19.For patients with hypertension,RAS-I and ARB applications were also associated with a reduced risk of mortality with HR of 0.352(95%CI 0.162–0.764)and 0.279(95%CI 0.115–0.677),respectively.RAS-I exhibited protective effects on the survival outcome of COVID-19.ARB use was associated with a reduced risk of all-cause mortality among patients with COVID-19.
