Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun

作     者：Wei Shao Shasha Li Lu Li Kequan Lin Xinhong Liu Haiyan Wang Huili Wang Dong Wang 

作者机构：Department of Basic Medical SciencesSchool of MedicineTsinghua UniversityBeijing 100084China Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversitySichuan 610041China Center for Synthetic and Systems BiologyTsinghua UniversityBeijing 100084China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2019年第10卷第3期

页      面：161-177页

核心收录：

学科分类：0710[理学-生物学] 0831[工学-生物医学工程（可授工学、理学、医学学位）] 1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 07[理学] 0703[理学-化学] 0836[工学-生物工程] 

基　　金：a grant from the National Natural Science Foundation of China(Grant No.81673460) fun ding from Tsinghua-Peking Joint Center for Life Sciences and Beijing Mun icipal Science&Technology Commissi on. 

主　　题：anti-metastatic drug discovery gene expression signature high-throughput sequencing-based high-throughput screening Ponatinib breast cancer lung metastasis c-Jun 

摘      要：Metastasis is the leading cause of human cancer deaths.Unfortunately,no approved drugs are available for antimetastatic treatment.In our study,high-throughput sequencing-based high-throughput screening(HTS^2)and a breast cancer lung metastasis(BCLM)-associated gene signature were combined to discover anti-metastatic drugs.After screening of thousands of compounds,we identified Ponatinib as a BCLM inhibitor.Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models.Mechanistically,Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein.Notably,JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients.Collectively,we established a novel approach for the discovery of anti-metastatic drugs,identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM.Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.