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