High-throughput screening identified pacritinib as a promising therapeutic approach to overcome lenvatinib resistance in hepatocellular carcinoma by targeting IRAK1

doi:10.1016/j.bbrc.2024.150782

科研成果详情

题名	High-throughput screening identified pacritinib as a promising therapeutic approach to overcome lenvatinib resistance in hepatocellular carcinoma by targeting IRAK1
作者	Li, Changyu1; Chen, Xiaoyu1,2; Wu, Jianghao1; Heng, Shan1; Xu, Zihao1; Gu, Hongyi1; Lin, Enhua1; Wang, Jiazhen1; Shan, Yunfeng1
发表日期	2024-11-19
发表期刊	Biochemical and Biophysical Research Communications 影响因子和分区
语种	英语
原始文献类型	Article
关键词	Pacritinib Lenvatinib Synergy JAK IRAK1 HCC
摘要	Lenvatinib resistance presents a significant challenge in the clinical management of advanced hepatocellular carcinoma (HCC). To address this issue, we established lenvatinib resistant HCC cells and performed highthroughput screening using FDA-approved anti-cancer drug library. Through quantitative selective drug sensitivity scoring (sDSS), pacritinib, a well-known JAK inhibitor, emerged as the top candidate, displaying the highest sDSS score among 219 compounds. We further demonstrated that pacritinib reduced the viability of a panel of HCC cell lines in a dose-dependent manner, while exhibiting minimal effects on normal liver cells. Interestingly, pacritinib, but not other JAK inhibitors such as ruxolitinib, upadacitinib, or filgotinib, acted synergistically with lenvatinib in HCC cells. In lenvatinib-resistant HCC cells, pacritinib significantly decreased proliferation and induced apoptosis. Rescue studies using IL-1 receptor-associated kinase 1 (IRAK1) overexpression and knockdown revealed that pacritinib's effects are mediated through IRAK1, with minimal impact on normal liver cells. In a xenograft model of lenvatinib-resistant HCC, oral administration of pacritinib significantly reduced tumor size without affecting body weight. Immunohistochemical analysis of tumor sections revealed that pacritinib reduced Ki67 staining and phosphorylated IRAK1. Our findings suggest that pacritinib may be a promising therapeutic option for the treatment of advanced HCC, particularly in patients who have developed resistance to lenvatinib.
资助项目	Wenzhou Medical University
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
ISSN	0006-291X
EISSN	1090-2104
卷号	734
DOI	10.1016/j.bbrc.2024.150782
页数	7
WOS类目	Biochemistry & Molecular Biology ; Biophysics
WOS研究方向	Biochemistry & Molecular Biology ; Biophysics
WOS记录号	WOS:001332114300001
收录类别	SCIE ; SCOPUS ; PUBMED
URL	查看原文
PubMed ID	39378786
SCOPUSEID	2-s2.0-85205707552
通讯作者地址	[Shan, Yunfeng]Wenzhou Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Wenzhou 325015, Zhejiang, Peoples R China.
Scopus学科分类	Biophysics;Biochemistry;Molecular Biology;Cell Biology
SCOPUS_ID	SCOPUS_ID:85205707552
引用统计
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/220782
专题	附属第一医院附属第一医院_肝胆外科
通讯作者	Shan, Yunfeng
作者单位	1.Wenzhou Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Wenzhou 325015, Zhejiang, Peoples R China; 2.Wenzhou Med Univ, Affiliated Hosp 1, Zhejiang Key Lab Intelligent Canc Biomarker Discov, Wenzhou, Zhejiang, Peoples R China
第一作者单位	附属第一医院; 肝胆外科
通讯作者单位	附属第一医院; 肝胆外科
第一作者的第一单位	附属第一医院
推荐引用方式 GB/T 7714	Li, Changyu,Chen, Xiaoyu,Wu, Jianghao,et al. High-throughput screening identified pacritinib as a promising therapeutic approach to overcome lenvatinib resistance in hepatocellular carcinoma by targeting IRAK1[J]. Biochemical and Biophysical Research Communications,2024,734.
APA	Li, Changyu., Chen, Xiaoyu., Wu, Jianghao., Heng, Shan., Xu, Zihao., ... & Shan, Yunfeng. (2024). High-throughput screening identified pacritinib as a promising therapeutic approach to overcome lenvatinib resistance in hepatocellular carcinoma by targeting IRAK1. Biochemical and Biophysical Research Communications, 734.
MLA	Li, Changyu,et al."High-throughput screening identified pacritinib as a promising therapeutic approach to overcome lenvatinib resistance in hepatocellular carcinoma by targeting IRAK1".Biochemical and Biophysical Research Communications 734(2024).