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SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer

文献类型：期刊论文

作者Zhou, Ji1,2; Zhang, Xu-Chao3,4; Xue, Shan5; Dai, Mengdi1,2; Wang, Yueliang1; Peng, Xia1; Chen, Jianjiao6; Wang, Xinyi1; Shen, Yanyan1; Qin, Hui5
刊名SIGNAL TRANSDUCTION AND TARGETED THERAPY
出版日期2023-05-15
卷号8期号:1页码:13
ISSN号2095-9907
DOI10.1038/s41392-023-01403-w
通讯作者Jiang, Handong(jianghd@163.com) ; Wu, Yi-Long(syylwu@live.cn) ; Geng, Meiyu(mygeng@simm.ac.cn) ; Ai, Jing(jai@simm.ac.cn)
英文摘要Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20-25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-beta 1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-beta 1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.
WOS关键词MESENCHYMAL TRANSITION ; ACQUIRED-RESISTANCE ; TYROSINE KINASE ; CHINESE PATIENTS ; OPEN-LABEL ; PHASE-II ; EGFR ; CRIZOTINIB ; NSCLC ; SENSITIVITY
资助项目Natural Science Foundation of China for Innovation Research Group[81821005] ; National Natural Science Foundation of China[81874314] ; National Natural Science Foundation of China[82173834] ; National Natural Science Foundation of China[82173202] ; Lingang Laboratory Grant ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] ; Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer[2017B030314120] ; Guangdong Provincial Natural Science Program[2019A1515010900] ; Guangdong Provincial Natural Science Program[DFJH201903] ; Guangdong Provincial Natural Science Program[KJ012019444] ; Guangdong Provincial Natural Science Program[8197103306]
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
出版者SPRINGERNATURE
WOS记录号WOS:000986497100001
源URL[http://119.78.100.183/handle/2S10ELR8/306466]  
专题新药研究国家重点实验室
通讯作者Jiang, Handong; Wu, Yi-Long; Geng, Meiyu; Ai, Jing
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.South China Univ Technol, Guangdong Prov Peoples Hosp, Guangdong Lung Canc Inst, Guangdong Prov Key Lab Translat Med Lung Canc, Guangzhou 510080, Peoples R China
4.South China Univ Technol, Guangdong Acad Med Sci, Sch Med, Guangzhou 510080, Peoples R China
5.Shanghai Jiao Tong Univ, Ren Ji Hosp, Sch Med, Dept Resp Med, Shanghai 200127, Peoples R China
6.Univ Pittsburgh, Brain Inst, Dept Neurobiol, Pittsburgh, PA 15213 USA
7.Xuzhou Med Univ, Dept Resp Med, Affiliated Hosp, Xuzhou 221000, Peoples R China
8.Fudan Univ, Minhang Hosp, Dept Resp Med, Shanghai 201199, Peoples R China
9.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Ji,Zhang, Xu-Chao,Xue, Shan,et al. SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2023,8(1):13.
APA Zhou, Ji.,Zhang, Xu-Chao.,Xue, Shan.,Dai, Mengdi.,Wang, Yueliang.,...&Ai, Jing.(2023).SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer.SIGNAL TRANSDUCTION AND TARGETED THERAPY,8(1),13.
MLA Zhou, Ji,et al."SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer".SIGNAL TRANSDUCTION AND TARGETED THERAPY 8.1(2023):13.

入库方式： OAI收割

来源：上海药物研究所

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