A multidimensional platform of patient-derived tumors identifies drug susceptibilities for clinical lenvatinib resistance

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外文摘要：Lenvatinib,a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer,facing limitations due to drug resistance.Here,we applied a multidimensional,high-throughput screening platform comprising patient-derived resistant liver tumor cells(PDCs),organoids(PDOs),and xenografts(PDXs)to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings.Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expe-diting drug repurposing screens.Pharmacological screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models.Notably,romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway.A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in hu-manized immunocompetent PDX models.Collectively,our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer,providing a feasible multidimensional platform for personalized medicine.

外文关键词：

LenvatinibDrug resistanceHigh-throughput screeningDrug discoveryPatient-derived modelRomidepsinEGFRLiver cancer

作者：

Lei Sun、Arabella H.Wan、Shijia Yan、Ruonian Liu、Jiarui Li、Zhuolong Zhou、Ruirui Wu、Dongshi Chen、Xianzhang Bu、Jingxing Ou、Kai Li、Xiongbin Lu、Guohui Wan、Zunfu Ke

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作者单位：

Department of Pathology,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510080,China

National-Local Joint Engineering Laboratory of Druggability and New Drug Evaluation,National Engineering Research Center for New Drug and Druggability(Cultivation),Guangdong Province Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

Department of Medical and Molecular Genetics,Indiana University School of Medicine,Indianapolis,IN 46202,USA

Department of Medicine,Keck School of Medicine,University of Southern California,Los Angeles,CA 90033,USA

Department of Hepatic Surgery and Liver Transplantation Center,Third Affiliated Hospital,Organ Transplantation Institute,Sun Yat-sen University,Organ Transplantation Research Center of Guangdong Province,Guangdong Province Engineering Laboratory for Transplantation Medicine,Guangzhou 510630,China

Guangdong Provincial Key Laboratory of Liver Disease Research,Guangzhou 510630,China

Department of Ultrasound,Third Affiliated Hospital,Sun Yat-sen University,Guangzhou 510630,China

Melvin and Bren Simon Comprehensive Cancer Center,Indiana University,Indianapolis,IN 46202,USA

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基金：

国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金Guangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research FoundationGuangdong Basic and Applied Basic Research Foundation中央高校基本科研业务费专项Opening Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation

项目编号：

821220698207386930900650813725018157226081773299H2808/823300652021B15150200042020B15151200322021B12120400172023B03J010623yxqntd0012020B1212060034

出版年：

2024

DOI：

10.1016/j.apsb.2023.09.015

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(1)

参考文献量67