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

doi:10.1093/nsr/nwae392

	Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target
	Wang, Hua 1,2; Tang, Shijie 1; Wu, Qibiao 1,2; He, Yayi 3; Zhu, Weikang 4; Xie, Xinyun 2,5,6; Qin, Zhen 1; Wang, Xue 1; Zhou, Shiyu 1; Yao, Shun 1; Xu, Xiaoling 7; Guo, Chenchen 1; Tong, Xinyuan 1; Han, Shuo 1; Chou, Yueh-Hung 8; Wang, Yong 4; Wong, Kwok-Kin 9; Yang, Cai-Guang 2,5,6; Chen, Luonan1,2,10,11 ; Hu, Liang 1; Ji, Hongbin1,2,10,11
	2024-12-16
发表期刊	NATIONAL SCIENCE REVIEW (IF:16.3[JCR-2023],18.6[5-Year])
ISSN	2095-5138
EISSN	2053-714X
卷号	11 期号:12
DOI	10.1093/nsr/nwae392
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.
关键词	EGFR-mutant lung cancer adeno-to-squamous transition tyrosine kinase inhibitor resistance transcription factor network RAPGEF3
URL	查看原文
收录类别	SCI ; EI
语种	英语
资助项目	National Key Research and Development Program of China["2022YFA1103900","2020YFA0803300","2022YFA1004800"] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB38040400] ; National Natural Science Foundation of China["82473426","82341002","32293192","82030083","82173340","82273400","32100593","82203306","82372763","82303916","82303039","T2341007","12131020","31930022","T2350003","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
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:001379161000001
出版者	OXFORD UNIV PRESS
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/464709
专题	生命科学与技术学院生命科学与技术学院_特聘教授组_季红斌组生命科学与技术学院_特聘教授组_陈洛南组
通讯作者	Yang, Cai-Guang; Chen, Luonan; Hu, Liang; Ji, Hongbin
作者单位	1.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, Key Lab Multicell Syst, Shanghai 200031, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Tongji Univ, Med Sch Canc Inst, Dept Med Oncol, Dept Med Oncol,Sch Med, Shanghai 200092, Peoples R China 4.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 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 7.Tongji Univ, Sch Med, Shanghai Pulm Hosp, Sch Med, Shanghai, Peoples R China 8.Far Eastern Mem Hosp, Dept Anat Pathol, New Taipei City, Taiwan 9.NYU, New York Univ Langone Hlth, Grossman Sch Med, Grossman Sch Med, New York, NY 10012 USA 10.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 11.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou 310024, Peoples R China
通讯作者单位	生命科学与技术学院
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).
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).
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).