DICP OpenIR
EGFR signaling confers resistance to BET inhibition in hepatocellular carcinoma through stabilizing oncogenic MYC
Yin, Yalei1; Sun, Mingju1; Zhan, Xi1,2; Wu, Changqing1; Geng, Pengyu1; Sun, Xiaoyan1,5,6,7,8; Wu, Yunsong1,4; Zhang, Shuijun5,6,7,8; Qin, Jianhua1; Zhuang, Zhengping3; Liu, Yang1,9
Corresponding AuthorLiu, Yang(yliuqq@dicp.ac.cn)
KeywordBromodomain JQ1 MAPK pathway MYC EGFR mutation Sorafenib
Source PublicationJOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
2019-02-15
ISSN1756-9966
DOI10.1186/s13046-019-1082-6
Volume38Pages:15
Funding ProjectNational Key Research and Development Program of China[2017YFC1308604] ; National Natural Science Foundation of China[81872446] ; Innovation program of science and research from the DICP, CAS[DICP TMSR201601] ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices[SDA16020900]
Funding OrganizationNational Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices ; strategic priority Research of the Chinese Academy of Scienices ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices ; strategic priority Research of the Chinese Academy of Scienices ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices ; strategic priority Research of the Chinese Academy of Scienices ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices ; strategic priority Research of the Chinese Academy of Scienices
WOS SubjectOncology
WOS Research AreaOncology
WOS KeywordC-MYC ; SORAFENIB ; CELLS ; JQ1 ; AMPLIFICATION ; THERAPY
AbstractBackgroundThe bromodomain and extra-terminal domain (BET) inhibitor is a type of anti-tumor agent, currently being evaluated in phase I and II clinical trials for cancer therapy. It can decrease MYC expression levels and cause effective anti-tumor effects in diverse human cancers. However, its cytotoxic effect and related mechanisms of drug resistance are poorly understood in hepatocellular carcinomas (HCC). Here, we investigated the anti-tumor effects of BET inhibitor on HCC and the molecular mechanisms involved in its associated drug resistance.MethodsWe assessed the cytotoxicity of BET inhibitor on HCC cells compared with sorafenib by cell viability assay, metastasis assay and reproduced the anti-tumor effect in xenograft mouse model. In addition, the molecular mechanisms involved in drug resistance on JQ1-resistant HCC cells were revealed by western blotting, qRT-PCR, whole exome-sequencing and gene-editing technology. Finally, with specific inhibition of EGFR or ERK activity by interference RNAs or inhibitors, the efficacy of the synergistic treatment was investigated using cell viability assay, colony formation, apoptosis and xenograft mouse model.ResultsWe found that JQ1, a commonly used BET bromo-domain inhibitor, offered a better anti-tumor response than sorafenib in MYC-positive HCC cells by inducing apoptosis in vitro and in vivo. Unlike sorafenib, JQ1 treatment significantly impaired mitochondrial respiration and glycolysis in HCC cells. Importantly, we revealed that MAPK activation by a previously undescribed activating mutation of EGFR-I645L, was critical for JQ1 sensitivity through stabilizing oncogenic MYC protein in JQ1-resistant HCC cells. Inhibition of either EGFR or ERK activity overcame the JQ1 resistance and significantly decreased MYC protein level in vitro and in vivo.ConclusionSince MYC amplification is frequently identified in HCC, co-occurring with EGFR amplification, our findings suggest that targeting EGFR signaling might be essential for JQ1 therapy in advanced HCC.
Language英语
Funding OrganizationNational Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices ; strategic priority Research of the Chinese Academy of Scienices ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices ; strategic priority Research of the Chinese Academy of Scienices ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices ; strategic priority Research of the Chinese Academy of Scienices ; National Key Research and Development Program of China ; National Key Research and Development Program of China ; National Natural Science Foundation of China ; National Natural Science Foundation of China ; Innovation program of science and research from the DICP, CAS ; Innovation program of science and research from the DICP, CAS ; 100 Talents Program of Chinese Academy of Sciences ; 100 Talents Program of Chinese Academy of Sciences ; strategic priority Research of the Chinese Academy of Scienices ; strategic priority Research of the Chinese Academy of Scienices
WOS IDWOS:000459069300001
PublisherBMC
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/165971
Collection中国科学院大连化学物理研究所
Corresponding AuthorLiu, Yang
Affiliation1.Chinese Acad Sci, Dalian Inst Chem Phys, Sci Res Ctr Translat Med, CAS Key Lab Separat Sci Analyt Chem, Dalian 116023, Peoples R China
2.Dalian Univ, Sch Life Sci, Dalian 116023, Peoples R China
3.NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA
4.Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Hubei, Peoples R China
5.Zhengzhou Univ, Dept Hepatobiliary & Pancreat Surg, Affiliated Hosp 1, Zhengzhou, Henan, Peoples R China
6.Zhengzhou Univ, Open & Key Lab Hepatobiliary & Pancreat Surg & Di, Affiliated Hosp 1, Zhengzhou, Henan, Peoples R China
7.Zhengzhou Key Lab Hepatobiliary & Pancreat Dis &, Zhengzhou, Henan, Peoples R China
8.Henan Key Lab Digest Organ Transplantat, Zhengzhou, Henan, Peoples R China
9.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
Recommended Citation
GB/T 7714
Yin, Yalei,Sun, Mingju,Zhan, Xi,et al. EGFR signaling confers resistance to BET inhibition in hepatocellular carcinoma through stabilizing oncogenic MYC[J]. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,2019,38:15.
APA Yin, Yalei.,Sun, Mingju.,Zhan, Xi.,Wu, Changqing.,Geng, Pengyu.,...&Liu, Yang.(2019).EGFR signaling confers resistance to BET inhibition in hepatocellular carcinoma through stabilizing oncogenic MYC.JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,38,15.
MLA Yin, Yalei,et al."EGFR signaling confers resistance to BET inhibition in hepatocellular carcinoma through stabilizing oncogenic MYC".JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 38(2019):15.
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