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Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target

文献类型：期刊论文

作者Wang, Hua10,11; Tang, Shijie11; Wu, Qibiao10,11; He, Yayi9; Zhu, Weikang8; Xie, Xinyun6,7,10; Qin, Zhen11; Wang, Xue11; Zhou, Shiyu11; Yao, Shun11
刊名NATIONAL SCIENCE REVIEW
出版日期2024-12-16
卷号11期号:12页码:20
关键词EGFR-mutant lung cancer adeno-to-squamous transition tyrosine kinase inhibitor resistance transcription factor network RAPGEF3
ISSN号2095-5138
DOI10.1093/nsr/nwae392
通讯作者Chen, Luonan(lnchen@sibcb.ac.cn) ; Hu, Liang(liang.hu@sibcb.ac.cn) ; Ji, Hongbin(hbji@sibcb.ac.cn)
英文摘要Although adeno-to-squamous transition (AST) has been observed in association with resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in clinic, its causality, molecular mechanism and overcoming strategies remain largely unclear. We here demonstrate that squamous transition occurs concomitantly with TKI resistance in PC9-derived xenograft tumors. Perturbation of squamous transition via DNp63 overexpression or knockdown leads to significant changes in TKI responses, indicative of a direct causal link between squamous transition and TKI resistance. Integrative RNA-seq, ATAC-seq analyses and functional studies reveal that FOXA1 plays an important role in maintaining adenomatous lineage and contributes to TKI sensitivity. FOXM1 overexpression together with FOXA1 knockout fully recapitulates squamous transition and TKI resistance in both PC9 xenografts and patient-derived xenograft (PDX) models. Importantly, pharmacological inhibition of RAPGEF3 combined with EGFR TKI efficiently overcomes TKI resistance, especially in RAPGEF3high PDXs. Our findings provide novel mechanistic insights into squamous transition and therapeutic strategy to overcome EGFR TKI resistance in lung cancer.
WOS关键词TYROSINE KINASE INHIBITORS ; CELL CARCINOMA ; ADENOCARCINOMA ; GEFITINIB ; MUTATION ; OSIMERTINIB ; ACTIVATION ; PLASTICITY ; EVOLUTION ; EPAC
资助项目National Key Research and Development Program of China[2022YFA1103900] ; National Key Research and Development Program of China[2020YFA0803300] ; National Key Research and Development Program of China[2022YFA1004800] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB38040400] ; National Natural Science Foundation of China[82473426] ; National Natural Science Foundation of China[82341002] ; National Natural Science Foundation of China[32293192] ; National Natural Science Foundation of China[82030083] ; National Natural Science Foundation of China[82173340] ; National Natural Science Foundation of China[82273400] ; National Natural Science Foundation of China[32100593] ; National Natural Science Foundation of China[82203306] ; National Natural Science Foundation of China[82372763] ; National Natural Science Foundation of China[82303916] ; National Natural Science Foundation of China[82303039] ; National Natural Science Foundation of China[T2341007] ; National Natural Science Foundation of China[12131020] ; National Natural Science Foundation of China[31930022] ; National Natural Science Foundation of China[T2350003] ; National Natural Science Foundation of China[82303575] ; Innovative research team of high-level local universities in Shanghai[SSMU-ZLCX2018050] ; Science and Technology Commission of Shanghai Municipality[23JS1401300] ; JST Moonshot RD[JPMJMS2021]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001379161000001
出版者OXFORD UNIV PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/315142]  
专题中国科学院上海药物研究所
通讯作者Chen, Luonan; Hu, Liang; Ji, Hongbin
作者单位1.NYU, New York Univ Langone Hlth, Grossman Sch Med, Grossman Sch Med, New York, NY 10012 USA
2.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou 310024, Peoples R China
3.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
4.Far Eastern Mem Hosp, Dept Anat Pathol, New Taipei City, Taiwan
5.Tongji Univ, Sch Med, Shanghai Pulm Hosp, Sch Med, Shanghai, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
8.Chinese Acad Sci, Acad Math & Syst Sci, Hua Loo Keng Ctr Math Sci, Ctr Excellence Math Sci,Natl Ctr Math & Interdisci, Beijing 100190, Peoples R China
9.Tongji Univ, Med Sch Canc Inst, Dept Med Oncol, Dept Med Oncol,Sch Med, Shanghai 200092, Peoples R China
10.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Hua,Tang, Shijie,Wu, Qibiao,et al. Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target[J]. NATIONAL SCIENCE REVIEW,2024,11(12):20.
APA Wang, Hua.,Tang, Shijie.,Wu, Qibiao.,He, Yayi.,Zhu, Weikang.,...&Ji, Hongbin.(2024).Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target.NATIONAL SCIENCE REVIEW,11(12),20.
MLA Wang, Hua,et al."Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target".NATIONAL SCIENCE REVIEW 11.12(2024):20.

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来源：上海药物研究所

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