Triple-negative breast cancer(TNBC)is an aggressive subtype characterized by resistance to conventional treatments and high recurrence rates.Cancer stem cells(CSCs)within TNBC contribute significantly to tumor progres...Triple-negative breast cancer(TNBC)is an aggressive subtype characterized by resistance to conventional treatments and high recurrence rates.Cancer stem cells(CSCs)within TNBC contribute significantly to tumor progression,metastasis,and therapy resistance.This study explores Enterolactone(EL),a bioactive phenolic metabolite from dietary lignans,as a potential therapeutic agent against TNBC-CSCs.The investigation began by identifying potential therapeutic targets for EL against TNBC-CSCs using predictive databases.A PPI network was constructed in STRING to emphasize top hub targets.Insights were derived from mRNA expression patterns,tumor stage differentials,and survival analysis via UALCAN and GEPIA2.Molecular docking and dynamics simulations were carried out to explore EL’s interactions with hub targets.GeneMANIA was employed to expand the target pool,generating two datasets.Preliminary FGN analysis and clustering of the second dataset were executed using GeneMANIA and MCODE plugins in CytoScape to enhance potential therapeutic avenues for EL against TNBC-CSCs.Employing network pharmacology,53 potential EL targets against TNBC-CSCs were identified,highlighting the top 15 hub targets,including ESR1,AKT1,JUN,EGFR,and others.Functional analysis unveiled their involvement in critical pathways like PI3K/AKT/mTOR,Wnt-βcatenin,and MAPK,essential for CSC self-renewal,metastasis,and therapy resistance.GO and KEGG analyses illuminated the biological significance of these targets,elucidating EL’s potential mechanisms.Analysis of GMFA-ED1 and-ED2 datasets expanded understanding,revealing novel targets of EL against TNBC-CSCs.In conclusion,EL demonstrates therapeutic potential against TNBC-CSCs by influencing crucial CSCs related molecular targets and Wnt-βcatenin and PI3K-AKT pathways,offering promising avenues in TNBC.展开更多
1文献来源研究一:Rudin CM,Poirier JT,Byers LA,et al.Molecular subtypes of small cell lung cancer:A synthesis of human and mouse model data[J].Nat Rev Cancer,2019,19(5):289-297.研究二:Owonikoko TK,Dwivedi B,Chen ZJ,et a...1文献来源研究一:Rudin CM,Poirier JT,Byers LA,et al.Molecular subtypes of small cell lung cancer:A synthesis of human and mouse model data[J].Nat Rev Cancer,2019,19(5):289-297.研究二:Owonikoko TK,Dwivedi B,Chen ZJ,et al.YAP1 positive small-cell lung cancer subtype is associated with the T-cell inflamed gene expression profile and confers good prognosis and long term survival[J].J Clin Oncol,2020,38(15S):Abstr 9019.展开更多
The discovery that mutations in the EGFR gene are detected in up to 50%of lung adenocarcinoma patients,along with the development of highly efficacious epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(...The discovery that mutations in the EGFR gene are detected in up to 50%of lung adenocarcinoma patients,along with the development of highly efficacious epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),has revolutionized the treatment of this frequently occurring lung malignancy.Indeed,the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy.Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC).The first-generation TKIs include erlotinib,gefitinib,lapatinib,and icotinib;the second-generation ErbB family blockers include afatinib,neratinib,and dacomitinib;whereas osimertinib,approved by the FDA on 2015,is a third-generation TKI targeting EGFR harboring specific mutations.Compared with the first-and second-generation TKIs,third-generation EGFR inhibitors display a significant advantage in terms of patient survival.For example,the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months.Unfortunately,however,like other targeted therapies,new EGFR mutations,as well as additional drug-resistance mechanisms emerge rapidly after treatment,posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance.In this review,we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance.We also discuss the current status of fourthgeneration EGFR inhibitors,which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.展开更多
1(NUTM1)gene rearrangements(15q14).In 1991,two independent research teams reported NC cases characterized by the t(15;19)translo-cation.1,2 In vitro studies by French et al.3 led to the pivotal discovery of NC in 2003...1(NUTM1)gene rearrangements(15q14).In 1991,two independent research teams reported NC cases characterized by the t(15;19)translo-cation.1,2 In vitro studies by French et al.3 led to the pivotal discovery of NC in 2003 as a distinct disease entity driven by the fusion of bromodo-main and extraterminal domain(BET)protein 4(BRD4)and NUTM1.In 2004,the World Health Organization(WHO)classified tumors with t(15;19)translocation as a thymic malignancy and designated it“NUT midline carcinoma,”due to its predominant occurrence in midline organs.4 However,subsequent reports revealed NC’s emergence in numerous nonmidline organs,leading to its reclassification as the independent entity“NUT carcinoma of the thorax”by the WHO in 2015.5 NC exhibits rapid progression and profound resistance to conventional radiotherapy and chemotherapy.展开更多
文摘Triple-negative breast cancer(TNBC)is an aggressive subtype characterized by resistance to conventional treatments and high recurrence rates.Cancer stem cells(CSCs)within TNBC contribute significantly to tumor progression,metastasis,and therapy resistance.This study explores Enterolactone(EL),a bioactive phenolic metabolite from dietary lignans,as a potential therapeutic agent against TNBC-CSCs.The investigation began by identifying potential therapeutic targets for EL against TNBC-CSCs using predictive databases.A PPI network was constructed in STRING to emphasize top hub targets.Insights were derived from mRNA expression patterns,tumor stage differentials,and survival analysis via UALCAN and GEPIA2.Molecular docking and dynamics simulations were carried out to explore EL’s interactions with hub targets.GeneMANIA was employed to expand the target pool,generating two datasets.Preliminary FGN analysis and clustering of the second dataset were executed using GeneMANIA and MCODE plugins in CytoScape to enhance potential therapeutic avenues for EL against TNBC-CSCs.Employing network pharmacology,53 potential EL targets against TNBC-CSCs were identified,highlighting the top 15 hub targets,including ESR1,AKT1,JUN,EGFR,and others.Functional analysis unveiled their involvement in critical pathways like PI3K/AKT/mTOR,Wnt-βcatenin,and MAPK,essential for CSC self-renewal,metastasis,and therapy resistance.GO and KEGG analyses illuminated the biological significance of these targets,elucidating EL’s potential mechanisms.Analysis of GMFA-ED1 and-ED2 datasets expanded understanding,revealing novel targets of EL against TNBC-CSCs.In conclusion,EL demonstrates therapeutic potential against TNBC-CSCs by influencing crucial CSCs related molecular targets and Wnt-βcatenin and PI3K-AKT pathways,offering promising avenues in TNBC.
文摘1文献来源研究一:Rudin CM,Poirier JT,Byers LA,et al.Molecular subtypes of small cell lung cancer:A synthesis of human and mouse model data[J].Nat Rev Cancer,2019,19(5):289-297.研究二:Owonikoko TK,Dwivedi B,Chen ZJ,et al.YAP1 positive small-cell lung cancer subtype is associated with the T-cell inflamed gene expression profile and confers good prognosis and long term survival[J].J Clin Oncol,2020,38(15S):Abstr 9019.
基金The study was supported by the Natural Science Foundation of Shanghai(No.20ZR1410400)the Extraordinary 2025 Elite Project of Fudan University,the National Natural Science Foundation of China(No.81772590 and 81572395)+1 种基金the Open Funding of Key Laboratory of Diagnosis and Treatment of Severe Hepato-pancreatic Diseases of Zhejiang Province(No.2018E10008)the CAS Interdisciplinary Innovation Team JCTD-2019-07.All figures showing EGFR kinase structure and binding modes were generated using PyMol 2.4.1(www.pymol.org).
文摘The discovery that mutations in the EGFR gene are detected in up to 50%of lung adenocarcinoma patients,along with the development of highly efficacious epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),has revolutionized the treatment of this frequently occurring lung malignancy.Indeed,the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy.Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC).The first-generation TKIs include erlotinib,gefitinib,lapatinib,and icotinib;the second-generation ErbB family blockers include afatinib,neratinib,and dacomitinib;whereas osimertinib,approved by the FDA on 2015,is a third-generation TKI targeting EGFR harboring specific mutations.Compared with the first-and second-generation TKIs,third-generation EGFR inhibitors display a significant advantage in terms of patient survival.For example,the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months.Unfortunately,however,like other targeted therapies,new EGFR mutations,as well as additional drug-resistance mechanisms emerge rapidly after treatment,posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance.In this review,we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance.We also discuss the current status of fourthgeneration EGFR inhibitors,which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.
基金supported by the China Postdoctoral Science Foundation(grant number 2022M723207)the Medical Scientific Research Foundation of Zhejiang Province,China(grant number 2023KY666)+8 种基金Zhejiang Traditional Chinese Medicine Science Fund Project(grant number 2024ZL372)Qiantang Cross Fund Project(grant number 2023-16)the National Natural Science Foundation of China of Zhejiang Cancer Hospital Cultivation Project(grant number PY2023006)the Medical Scientific Research Foundation of Zhejiang Province,China(grant number 2024KY812)the Natural Science Foundation of Zhejiang Province(grant number Q24H160110)the National Natural Science Foundation of China(grant number NSFC82371851)the Science and Technology Foundation of Guizhou Province(Outstanding Young Scientists of Guizhou Province)(grant number Qiankeherencai-YQK(2023)021)the Science and Technology Foundation of Guizhou Province(grant number Qiankehejichu-ZK(2023)General 212)the Science and Technology Foundation of Guizhou Province(grant number Qiankehechengguo-LC(2025)General 068).
文摘1(NUTM1)gene rearrangements(15q14).In 1991,two independent research teams reported NC cases characterized by the t(15;19)translo-cation.1,2 In vitro studies by French et al.3 led to the pivotal discovery of NC in 2003 as a distinct disease entity driven by the fusion of bromodo-main and extraterminal domain(BET)protein 4(BRD4)and NUTM1.In 2004,the World Health Organization(WHO)classified tumors with t(15;19)translocation as a thymic malignancy and designated it“NUT midline carcinoma,”due to its predominant occurrence in midline organs.4 However,subsequent reports revealed NC’s emergence in numerous nonmidline organs,leading to its reclassification as the independent entity“NUT carcinoma of the thorax”by the WHO in 2015.5 NC exhibits rapid progression and profound resistance to conventional radiotherapy and chemotherapy.
