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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 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,expediting 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 humanized 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.

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 characterized.Here,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 migration.We 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 migration.Notably,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)sites.Our 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 substitution.Here,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 pattern.Furthermore,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 injury.In contrast,erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3.This study reveals that FOXO3 mutation,leading to autophagic imbalance,plays important role in gefitinib-induced hepatotoxicity,especially for patients with high concentration of gefitinib.In 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 dose.Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation.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 BAP1.Accumulated 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 defined.Through activity-based profiling,we identified PT33 as an active entity for HR repair suppression.Subsequently,we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen.Mechanistically,pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction,interrupting HR repair.Consequently,PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo.Overall,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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小攻角下锯齿尾缘翼型噪声控制与机理分析

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实验流体力学 2024年第1期38卷 28-36页

作者：胡亚森张彭俊燚庄国徽万振华孙德军中国科学技术大学近代力学系合肥230027

受猫头鹰寂静飞行能力的启发,锯齿尾缘设计被认为是一种有效的控制湍流边界层-尾缘干涉噪声的方法。本文采用隐式大涡模拟法,详细研究了嵌入式锯齿尾缘对NACA 0012翼型绕流的近场流动和噪声特性的影响,雷诺数为9.6×10^(4),远场马赫数为... 详细信息

受猫头鹰寂静飞行能力的启发,锯齿尾缘设计被认为是一种有效的控制湍流边界层-尾缘干涉噪声的方法。本文采用隐式大涡模拟法,详细研究了嵌入式锯齿尾缘对NACA 0012翼型绕流的近场流动和噪声特性的影响,雷诺数为9.6×10^(4),远场马赫数为0.1631,攻角为4°,计算采用的非结构化网格具有约7000万的自由度。在实际计算时,为促进流动快速转捩,在直尾缘和锯齿尾缘算例的翼型表面均布置了锯齿形粗糙元转捩带。研究结果表明:相比于0°攻角状态,4?攻角下的噪声辐射增强,主辐射方向发生偏转,在该方向上锯齿尾缘实现了约2.5 dB的降噪,且在小攻角(4°)下,锯齿也会诱导出有利于降噪的侧边涡对结构。针对壁面压力脉动的分析表明:锯齿主要改变了尾缘附近的时空关联特性,且压力场不能直接由现有针对速度场的Taylor或椭圆近似模型定量描述;此外,锯齿在抑制尾缘噪声的同时,对翼型气动性能造成了一定损失。

关键词：气动噪声锯齿尾缘噪声控制可压缩湍流

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Effect of solvent on directional drift in Brownian motion of particle/molecule with broken symmetry

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Science China(Physics,Mechanics & Astronomy) 2016年第8期59卷 28-33页

作者： FanDong Kong Nan Sheng RongZheng wan guohui Hu HaiPing Fang Shanghai Institute of Applied Mathematics and Mechanics Shanghai Key Laboratory of Mechanics in Energy EngineeringShanghai University Division of Interfacial Water and Key Laboratory of Interfacial Physics and Technology Shanghai Institute of Applied PhysicsChinese Academy of Sciences

The directional drifting of particles/molecules with broken symmetry has received increasing attention. Through molecular dynamics simulations, we investigate the effects of various solvents on the time-dependent directional drifting of a particle with broken symmetry. Our simulations show that the distance of directional drift of the asymmetrical particle is reduced while the ratio of the drift to the mean displacement of the particle is enhanced with increasing mass, size, and interaction strength of the solvent atoms in a short time range. Among the parameters considered, solvent atom size is a particularly influential factor for enhancing the directional drift of asymmetrical particles, while the effects of the interaction strength and the mass of the solvent atoms are relatively weaker. These findings are of great importance to the understanding and control of the Brownian motion of particles in various physical, chemical, and biological processes within finite time spans.

关键词： Brownian粒子分子动力学模拟对称破缺漂移溶剂运动方向相互作用强度对称性破缺

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Asymmetric self-diffusion with orientation-dependence of water molecule in finite timescale

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Science China(Physics,Mechanics & Astronomy) 2016年第7期59卷 20-24页

作者： Xu Wei Nan Sheng RongZheng wan guohui Hu HaiPing Fang Shanghai Institute of Applied Mathematics and Mechanics Shanghai University Division of Interfacial Water and Key Laboratory of Interfacial Physics and Technology Shanghai Institute of Applied PhysicsChinese Academy of Sciences

Self-diffusion of water has been investigated by molecular dynamics simulations.It was found that the preference of the direction in self-diffusion of water is orientation dependent in a finite time.For a time of^100 ps,there are more possibilities for water molecules moving along the initial dipole orientation than in the opposite direction.This reveals that self-diffusion of water molecules is asymmetric in a finite time.We tested four water models and found that they all show similar asymmetric diffusion,indicating that asymmetric diffusion of water is intrinsic behavior rather than induced by the water model.These results are important for understanding and application of asymmetric diffusion in research fields such as biological water and confined water in small dimensions.

关键词：时间尺度自扩散水分子非对称分子动力学模拟偶极子取向时间依赖水模型

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A New Growth Model of Fault Attributes in a Strike-Slip Fault System in the Tarim Basin

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Acta Geologica Sinica(English Edition) 2020年第5期94卷 1373-1380页

作者： ZHANG Yintao WU Guanghui wanG Junfang LI guohui wan Xiaoguo YANG Tianyi School of Geoscience and Technology Southwest Petroleum UniversityChengdu 610500China PetroChina Tarim Oilfield Company KorlaXinjiang 841000China PetroChina Key Laboratory of Carbonate Reservoir Southwest Petroleum UniversityChengdu 610500China

Fault attributes generally display a consistent power–law-scaling relationship.Based on new 3 D seismic data,however,we found some exceptional fault attribute relationships of lengths(L)–throw(T)(vertical component of displacement),overlap zone length(Lo)–width(Wo)from a strike-slip fault system of the Ordovician carbonates in the Tarim Basin.The L–T relationship shows two linear segments with breakup at^40 km in fault length.This presents an exceptional throw increase in the second stage,which is attributed to a localization of vertical displacement and deformation in overlapping zones other than the different fault scales in a mature fault zone.The Lo–Wo relationship in the overlapping zones shows multiply stepped-shape patterns,suggesting multiple fault differential growth and periodic increase in fault size.Therefore,we propose a new alternative growth model of fault attributes in strike-slip fault zones,in which the overlapping zones accumulated localized displacement and deformation in the intracratonic strike-slip fault zone.

关键词： fault modeling fault attributes strike-slip fault overlapping zone power-law-scaling fault growth process

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Nucleocytoplasmic Trafficking of the Arabidopsis WD40 Repeat Protein XIW1 Regulates ABI5 Stability and Abscisic Acid Responses

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Molecular Plant 2019年第12期12卷 1598-1611页

作者： Xuezhong XU wang wan Guobin Jiang Yue Xi Haijian Huang Jiajia Cai Yanan Chang Cheng-Guo Duan Satendra KMangrauthia Xinxiang Peng Jian-Kang Zhu guohui Zhu College of Life Sciences South China Agricultural UniversityGuangzhou 510642China Shanghai Center for Plant Stress Biology and Center of Excellence for Molecular Plant Sciences Chinese Academy of SciencesShanghai 201602China Biotechnology Section Indian Institute of Rice ResearchHyderabad 500030India State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources South China Agricultural UniversityGuangzhou 510642China Department of Horticulture and Landscape Architecture Purdue UniversityWest LafayetteIN 47907USA Guangdong Provincial Key Laboratory of Protein Function and Regulation in

WD40 repeat-containing proteins(WD40 proteins)serve as versatile scaffolds for protein-protein interac-tions,modulating a variety of cellular processes such as plant stress and hormone responses.Here we report the identification of a WD40 protein,XIW1(for XPO1-interacting WD40 protein 1),which positively regulates the abscisic acid(ABA)response in Arabidopsis.XIW1 is located in the cytoplasm and nucleus.We found that it interacts with the nuclear transport receptor XPO1 and is exported by XPO1 from the nucleus.Mutation of XIW1 reduces the induction of ABA-responsive genes and the accumulation of ABA Insensitive 5(ABI5),causing mutant plants with ABA-insensitive phenotypes during seed germination and seedling growth,and decreased drought stress resistance.ABA treatment upregulates the expression of XIW1,and both ABA and abiotic stresses promote XIW1 accumulation in the nucleus,where it interacts with ABI5.Loss of XIW1 function results in rapid proteasomal degradation of ABI5.Taken together,these findings suggest that XIW1 is a nucleocytoplasmic shuttling protein and plays a positive role in ABA responses by interacting with and maintaining the stability of ABI5 in the nucleus.

关键词： WD40 protein ABA signaling nuclear export ABI5 stability XPO1

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