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

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Acta Pharmaceutica Sinica B 2024年第1期14卷 223-240页

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 Department of Pathology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China 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 EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China Department of Medical and Molecular Genetics Indiana University School of MedicineIndianapolisIN 46202USA Department of Medicine Keck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90033USA Department of Hepatic Surgery and Liver Transplantation Center Third Affiliated HospitalOrgan Transplantation InstituteSun Yat-sen UniversityOrgan Transplantation Research Center of Guangdong ProvinceGuangdong Province Engineering Laboratory for Transplantation MedicineGuangzhou 510630China Guangdong Provincial Key Laboratory of Liver Disease Research Guangzhou 510630China Department of Ultrasound Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China Melvin and Bren Simon Comprehensive Cancer Center Indiana UniversityIndianapolisIN 46202USA

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 ***,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 *** and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment,expediting drug repurposing *** screening identified romidepsin,YM155,apitolisib,NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO ***,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 humanized immunocompetent PDX ***,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.

关键词： Lenvatinib Drug resistance High-throughput screening Drug discovery Patient-derived model Romidepsin EGFR Liver cancer

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Disruption of PABPN1 phase separation by SNRPD2 drives colorectal cancer cell proliferation and migration through promoting alternative polyadenylation of CTNNBIP1

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Science China(Life Sciences) 2024年第6期67卷 1212-1225页

作者： Zhijie Hu Mengxia Li Yufeng Chen Liutao Chen Yuting Han Chengyong Chen Xin Lu Nan You Yawen Lou Yingye Huang Zhanfeng Huo Chao Liu Cheng Liang Susu Liu Ke Deng Liangfu Chen Shangwu Chen guohui wan Xiaojian Wu Yonggui Fu Anlong Xu State Key Laboratory of Biocontrol Guangdong Province Key Laboratory of Pharmaceutical Functional GenesDepartment of BiochemistrySchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China Department of General Surgery(Colorectal Surgery)&Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases&Biomedical Innovation Center The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China 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 EvaluationSchool of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510006China School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China

Generally shortened 3′UTR due to alternative polyadenylation(APA)is widely observed in cancer,but its regulation mechanisms for cancer are not well ***,with profiling of APA in colorectal cancer tissues and poly(A)signal editing,we firstly identified that the shortened 3′UTR of CTNNIBP1 in colorectal cancer promotes cell proliferation and *** found that liquid-liquid phase separation(LLPS)of PABPN1 is reduced albeit with higher expression in cancer,and the reduction of LLPS leads to the shortened 3′UTR of CTNNBIP1and promotes cell proliferation and ***,the splicing factor SNRPD2 upregulated in colorectal cancer,can interact with glutamic-proline(EP)domain of PABPN1,and then disrupt LLPS of PABPN1,which attenuates the repression effect of PABPN1 on the proximal poly(A)*** results firstly reveal a new regulation mechanism of APA by disruption of LLPS of PABPN1,suggesting that regulation of APA by interfering LLPS of 3′end processing factor may have the potential as a new way for the treatment of cancer.

关键词： alternative polyadenylation colorectal cancer CTNNBIP1 PABPN1 liquid-liquid phase separation SNRPD2

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N^6-Methyladenosine modification: a novel pharmacological target for anti-cancer drug development

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Acta Pharmaceutica Sinica B 2018年第6期8卷 833-843页

作者： Yi Niu Arabella wan Ziyou Lin Xiongbin Lu guohui wan School of Pharmaceutical Sciences Sun Yat-Sen University School of Medical Laboratory Science Pennsylvania Hospital Department of Medical and Molecular Genetics Indiana University School of Medicine Indiana University Melvin and Bren Simon Cancer Center

N6-Methyladenosine(m6 A) modification is the most pervasive modification of human mRNA molecules. It is reversible via regulation of m6 A modification methyltransferase, demethylase and proteins that preferentially recognize m6 A modification as "writers", "erasers" and "readers", respectively. Altered expression levels of the m6 A modification key regulators substantially affect their function, leading to significant phenotype changes in the cell and organism. Recent studies have proved that the m6 A modification plays significant roles in regulation of metabolism, stem cell self-renewal, and metastasis in a variety of human cancers. In this review, we describe the potential roles of m6 A modification in human cancers and summarize their underlying molecular mechanisms. Moreover, we will highlight potential therapeutic approaches by targeting the key m6 A modification regulators for cancer drug development.& 2018 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license(http://***/licenses/by-nc-nd/4.0/).

关键词： N^6-Methyladenosine Human cancer Pharmacological target m^6A modification regulator Drug development

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FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3639-3649页

作者： Shaoxing Guan Xi Chen Youhao Chen guohui wan Qibiao Su Heng Liang Yunpeng Yang Wenfeng Fang Yan Huang Hongyun Zhao Wei Zhuang Shu Liu Fei wang Wei Feng Xiaoxu Zhang Min Huang Xueding wang Li Zhang Laboratory of Drug Metabolism and Pharmacokinetics School of Pharmaceutical SciencesSun Yat-sen UniversityGuangzhou 510060China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China College of Health Science Guangdong Pharmaceutical UniversityGuangzhou 510006China Sun Yat-sen Memorial Hospital Sun Yat-sen UniversityGuangzhou 510080China Ersha Department of Pharmacy the Second Affiliated Hospital of Guangzhou University of Chinese MedicineGuangzhou 510105China

Hepatotoxicity is a common side effect for patients treated with gefitinib,but the related pathogenesis is unclear and lacks effective predictor and management strategies.A multi-omics approach integrating pharmacometabolomics,pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy ***,we found that patients with rs4946935 AA,located in Forkhead Box O3(FOXO3)which is a well-known autophagic regulator,had a higher risk of hepatotoxicity than those with the GA or GG variant(OR=18.020,95%CI=2.473 to 459.1784,P=0.018)in a gefitinib-concentration dependent ***,functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity,increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver *** contrast,erlotinib-induced liver injury was independent on the variant and expression levels of *** study reveals that FOXO3 mutation,leading to autophagic imbalance,plays important role in gefitinib-induced hepatotoxicity,especially for patients with high concentration of *** conclusion,FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.

关键词： Gefitinib Hepatotoxicity Pharmacometabolomic Pharmacokinetics Pharmacogenomics FOXO3 Autophagy

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Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3382-3399页

作者： Xin Yue Tingyu Liu Xuecen wang Weijian Wu Gesi Wen Yang Yi Jiaxin Wu Ziyang wang Weixiang Zhan Ruirui Wu Yuan Meng Zhirui Cao Liyuan Le Wenyan Qiu Xiaoyue Zhang Zhenyu Li Yong Chen guohui wan Xianzhang Bu Zhenwei Peng Ran-yi Liu State Key Laboratory of Oncology in South China Sun Yat-sen University Cancer CenterGuangzhou 510060China Department of Radiation Oncology the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China Department of Clinical Research Guangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China Department of Gastrointestinal Surgery the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Department of Oncology the Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China Department of Traditional Chinese Medicine the First Affiliated HospitalSun Yat-sen UniversityGuangzhou 510080China Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhou 510080China Laboratory of Chemical Oncogenomics Guangdong Provincial Key Laboratory of Chemical GenomicsPeking University Shenzhen Graduate SchoolShenzhen 518055China

Radiotherapy is widely used in the management of advanced colorectal cancer(CRC).However,the clinical efficacy is limited by the safe irradiated *** tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the *** BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination(HR)DSB repair,and its functions may be affected by HERC2 or *** evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes;however,the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn’t been *** activity-based profiling,we identified PT33 as an active entity for HR repair ***,we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase ***,pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction,interrupting HR ***,PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in ***,these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

关键词： Pharmacological inhibition BAP1 HERC2recruitment BRCA1 BARD1 Competitively dissociation HR-Mediated DNArepair,CRCradiosensitization

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化学法去除循环水排污水中的磷

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化工环保 2016年第5期36卷 523-526页

作者：赵辉邱小云龚小芝万国晖中国石化北京化工研究院环保所北京100013

研究了聚合氯化铝、硫酸铁、氯化铁及生石灰等除磷剂对循环水排污水的除磷效果,考察了反应温度、反应时间、污水p H和除磷剂投加方式对除磷效果的影响。实验结果表明:聚合氯化铝和硫酸铁的除磷效率相当,其次是氯化铁,生石灰的除磷效率最... 详细信息

研究了聚合氯化铝、硫酸铁、氯化铁及生石灰等除磷剂对循环水排污水的除磷效果,考察了反应温度、反应时间、污水p H和除磷剂投加方式对除磷效果的影响。实验结果表明:聚合氯化铝和硫酸铁的除磷效率相当,其次是氯化铁,生石灰的除磷效率最低;最终选用聚合氯化铝作为除磷剂,对循环水排污水进行除磷处理时无需调节其p H,反应可在室温下进行,反应时间需大于300 s;聚合氯化铝最佳投加量为40 mg/L,二次性投加聚合氯化铝的除磷效果明显好于一次性投加;二次性投加出水TP为0.37 mg/L。

关键词：循环水排污水除磷剂总磷聚合氯化铝

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用环己酮废水合成阳离子沥青乳化剂

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化工环保 2012年第3期32卷 251-254页

作者：李昕阳李正琪万国晖中国石化北京化工研究院环保所北京100013

以环己酮生产废水(以下简称废水)为溶剂,以木质素、三乙烯四胺及甲醛为原料,通过Mannich反应制备了阳离子沥青乳化剂木质素胺。实验结果表明,制备木质素胺的最佳工艺条件为:反应温度85℃,反应时间5 h,n(甲醛):n(三乙烯四胺)=3.0。经FTI... 详细信息

以环己酮生产废水(以下简称废水)为溶剂,以木质素、三乙烯四胺及甲醛为原料,通过Mannich反应制备了阳离子沥青乳化剂木质素胺。实验结果表明,制备木质素胺的最佳工艺条件为:反应温度85℃,反应时间5 h,n(甲醛):n(三乙烯四胺)=3.0。经FTIR表征,以废水为溶剂和以去离子水为溶剂所制备的木质素胺结构相同。以实验制备的木质素胺为乳化剂制成的乳化沥青的性能指标达到JTG E20—2011《公路工程沥青及沥青混合料试验规程》的指标。

关键词：环己酮废水沥青乳化剂木质素胺乳化沥青综合利用

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石化厂污水反渗透浓水的催化臭氧氧化处理

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化工环保 2012年第5期32卷 428-431页

作者：龚小芝赵辉万国晖刘正栾金义中国石化北京化工研究院环保所北京100013

针对某炼油厂二沉池出水回用过程中产生的反渗透浓水高盐、高硬、低COD和可生化性差的特点,采用催化臭氧氧化工艺处理,出水达标排放。实验确定了对臭氧氧化催化效果最好的催化剂,合适的反应条件为:反应时间大于30 min,臭氧质量浓度15～3... 详细信息

针对某炼油厂二沉池出水回用过程中产生的反渗透浓水高盐、高硬、低COD和可生化性差的特点,采用催化臭氧氧化工艺处理,出水达标排放。实验确定了对臭氧氧化催化效果最好的催化剂,合适的反应条件为:反应时间大于30 min,臭氧质量浓度15～30 mg/L。经催化臭氧氧化处理后,反渗透浓水的COD降低至60 mg/L以下,满足排放要求,同时反渗透浓水可生化性提高。

关键词：反渗透浓水催化臭氧氧化排放废水处理

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纳滤处理炼化污水反渗透浓水

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化工环保 2015年第4期35卷 386-390页

作者：邱小云刘正万国晖赵辉龚小芝中国石化北京化工研究院环保所北京100013

分别采用4种纳滤膜处理某炼化公司的反渗透浓水。在初始COD为57．8mg／L、TOC为23．94mg／L、P（ca2＋）为289．0mg／L、P（Mg2＋）为54．6mg／L、P（soi）为327．7mg／L、P（Cl-）为1106．8mg／L的条件下，经纳滤处理后COD去除率达60... 详细信息

分别采用4种纳滤膜处理某炼化公司的反渗透浓水。在初始COD为57．8mg／L、TOC为23．94mg／L、P（ca2＋）为289．0mg／L、P（Mg2＋）为54．6mg／L、P（soi）为327．7mg／L、P（Cl-）为1106．8mg／L的条件下，经纳滤处理后COD去除率达60％以上，污水COD降至30mg／L以下，TOC去除率为31．9％∽85．5％，阳离子的去除率为33．9％∽97．0％，SO4 2-的去除率为63.3％∽97．6％，Cl-的去除率较低。膜A的膜孔分布密集，具有很高的通量，对有机物和无机盐的截留效果较差；膜B和膜C对有机物和二价离子的截留效果较好；膜D的膜孔分布稀松，膜通量最低，对有机物和无机盐的截留能力均较强，但随出水体积的增加，对无机盐的截留能力下降较为明显。4种纳滤膜的性能各异，可满足不同企业的需求，具有良好的应用前景。

关键词：纳滤膜反渗透浓水炼化污水无机盐

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低氧诱导的HIF-1α对结肠癌细胞生长代谢的影响及其调控机制

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实用医学杂志 2020年第8期36卷 1035-1040页

作者：何伟玲李清海严时佳万国辉中山大学附属第一医院胃肠外科广州510080 中山大学药学院广州510006

目的低氧环境下肿瘤细胞生长代谢异常,探讨低氧诱导因子(hypoxia inducible factor 1,HIF)对岩藻糖基转移酶Ⅳ(fucosyltransferase4,FUT4)的负性调控机制及病理生理意义。方法前期从基因表达数据库中筛选到符合研究条件的芯片GSE77606,... 详细信息

目的低氧环境下肿瘤细胞生长代谢异常,探讨低氧诱导因子(hypoxia inducible factor 1,HIF)对岩藻糖基转移酶Ⅳ(fucosyltransferase4,FUT4)的负性调控机制及病理生理意义。方法前期从基因表达数据库中筛选到符合研究条件的芯片GSE77606,结合京都基因与基因组百科全书通路富集分析,发现低氧环境下结肠癌(colon cancer)细胞生长代谢异常,FUT4表达明显下降;随后通过TargetScan数据库筛选出与FUT4信使RNA序列互补的微小RNA(miRNA),并结合定量RT-PCR(QRT-PCR)、荧光素酶报告基因实验及突变实验、短发夹RNA干扰实验和miRNA沉默和过表达实验等探索其具体的调控机制。结果QRT-PCR证实低氧培养HCT-116细胞明显低表达FUT4(P <0.001);TargetScan数据库筛选结合荧光素酶报告基因实验和突变实验证实hsa-miRNA-23a-3p可靶向FUT4信使RNA并下调其表达(P <0.05),同时QRT-PCR显示低氧环境可诱导hsa-miRNA-23a-3p的表达(P <0.05);短发夹RNA干扰实验证实hsa-miRNA-23a-3p的表达受到HIF-1α的正性调控(P <0.01);最后hsa-miRNA-23a-3p沉默或过表达实验进一步证实了hsa-miRNA-23a-3p可正反调控FUT4的表达水平(P <0.001)。结论结肠癌细胞在低氧环境中通过HIF-1α诱导has-miRNA-23a-3p下调FUT4的表达,影响代谢调控,降低细胞侵袭性。

关键词：岩藻糖基转移酶Ⅳ hsa-miRNA-23a-3p 低氧诱导因子-1α 结肠癌

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