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A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma

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Frontiers of Medicine 2023年第2期17卷 275-289页

作者： Jing Yang Yanfei Yang Yuquan Wei Xiawei wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China Melanoma and Sarcoma Medical Oncology Unit State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer MedicineSun Yat-sen University Cancer CenterGuangzhou 510060China Department of Gynecology and Obstetrics The Third Xiangya HospitalCentral South UniversityChangsha 410008China

The abnormal activation of HER family kinase activity is closely related to the development of human malignancies.In this study,we used HER kinases as targets for the treatment of nasopharyngeal carcinoma(NPC)and explored the anti-tumor effects of the novel pan-HER inhibitor HM781-36B,alone or in combination with cisplatin.We found that HER family proteins were positively expressed in tumor tissues of some NPC patients,and the high levels of those proteins were significantly related to poor prognosis.HM781-36B inhibited NPC in vitro and in vivo.HM781-36B exerted synergistic effects with cisplatin on inhibiting proliferation and promoting apoptosis of NPC cells.In NPC xenograft models in nude mice,HM781-36B and cisplatin synergistically inhibited tumor growth.Downregulating the activity of HER family proteins and their downstream signaling pathways and regulating tumor microenvironment may explain the synergistic anti-tumor effects of HM781-36B and cisplatin.In conclusion,our study provides evidence for HER family proteins as prognostic biomarkers and potential therapeutic targets for NPC.The pan-HER inhibitor HM781-36B alone or in combination with cisplatin represents promising therapeutic effects for the treatment of NPC patients,which provides a new idea for the comprehensive treatment of NPC.

关键词： epidermal growth factor receptor ErbB receptors HM781-36B nasopharyngeal carcinoma molecular targeted therapy cisplatin

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Opportunities and challenges in the nanoparticles for nucleic acid therapeutics: the first approval of an RNAi nanoparticle for treatment of a rare disease

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National Science Review 2019年第6期6卷 1105-1106页

作者： Xiawei wei Yuquan Wei Laboratory of Aging Research and Nanotoxicology State Key Laboratory of Biotherapy National Clinical Research Center for Geriatrics West China Hospital Sichuan University

Nanoparticle-based nucleic acid therapeutics have drawn considerable attention over recent decades. By using terms such as ‘nanoparticle’ and ‘gene delivery’ in a Pub Med search, we found that 10 years ago throughout 2008 there were only 725 such papers published;however, in 2017, over 4700 papers were published with the same keywords.

关键词： the first approval of an RNAi nanoparticle for treatment of a rare disease Opportunities and challenges in the nanoparticles for nucleic acid therapeutics

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Multifunctional regulatory protein connective tissue growth factor (CTGF):A potential therapeutic target for diverse diseases

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1740-1760页

作者： Minyang Fu Dandan Peng Tianxia Lan Yuquan Wei Xiawei wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

Connective tissue growth factor(CTGF),a multifunctional protein of the CCN family,regulates cell proliferation,differentiation,adhesion,and a variety of other biological processes.It is involved in the disease-related pathways such as the Hippo pathway,p53 and nuclear factor kappa-B(NF-κB)pathways and thus contributes to the developments of inflammation,fibrosis,cancer and other diseases as a downstream effector.Therefore,CTGF might be a potential therapeutic target for treating various diseases.In recent years,the research on the potential of CTGF in the treatment of diseases has also been paid more attention.Several drugs targeting CTGF(monoclonal antibodies FG3149 and FG3019)are being assessed by clinical or preclinical trials and have shown promising outcomes.In this review,the cellular events regulated by CTGF,and the relationships between CTGF and pathogenesis of diseases are systematically summarized.In addition,we highlight the current researches,focusing on the preclinical and clinical trials concerned with CTGF as the therapeutic target.

关键词： CTGF CCN2 CCN family Fibrosis Cancer Targeted therapy Immunotherapy Therapeutic strategies

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Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer:Current status in clinical trials

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Genes & Diseases 2023年第1期10卷 76-88页

作者： Yanlin Song Zhenfei Bi Yu Liu Furong Qin Yuquan Wei Xiawei wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuan610041China

Molecular target inhibitors have been regularly approved by Food and Drug Administration(FDA)for tumor treatment,and most of them intervene in tumor cell proliferation and metabolism.The RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation,survival,and differentiation.The aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces tumors.About 33%of tumors harbor RAS mutations,while 8%of tumors are driven by RAF mutations.Great efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past decades.In this review,we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical treatment.Moreover,we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling pathways.The inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancerresearchandtreatment.

关键词： Clinical trials Molecular target therapy RAS-RAF-MEK-ERK signaling pathway

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DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3935-3949页

作者： Manni Wang Siyuan Chen Yuquan Wei Xiawei wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610000China

A significant proportion of non-small cell lung cancer(NSCLC) patients experience accumulating chemotherapy-related adverse events,motivating the design of chemosensitizating strategies.The main cytotoxic damage induced by chemotherapeutic agents is DNA double-strand breaks(DSB).It is thus conceivable that DNA-dependent protein kinase(DNA-PK) inhibitors which attenuate DNA repair would enhance the anti-tumor effect of chemotherapy.The present study aims to systematically evaluate the efficacy and safety of a novel DNA-PK inhibitor M3814 in synergy with chemotherapies on NSCLC.We identified increased expression of DNA-PK in human NSCLC tissues which was associated with poor prognosis.M3814 potentiated the anti-tumor effect of paclitaxel and etoposide in A549,H460 and H1703 NSCLC cell lines.In the four combinations based on two NSCLC xenograft models and two chemotherapy,we also observed tumor regression at tolerated doses in vivo.Moreover,we identified a P53-dependent accelerated senescence response by M3814 following treatment with paclitaxel/etoposide.The present study provides a theoretical basis for the use of M3814 in combination with paclitaxel and etoposide in clinical practice,with hope to aid the optimization of NSCLC treatment.

关键词： M3814 Paclitaxel Etoposide DNA-dependent protein kinase Non-small cell lung cancer DNA repair Cell senescence Chemosensitization

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Diversity of the reaction mechanisms of SAM-dependent enzymes

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Acta Pharmaceutica Sinica B 2021年第3期11卷 632-650页

作者： Qiu Sun Mengyuan Huang Yuquan Wei State Key Laboratory of Biotherapy Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

S-adenosylmethionine(SAM) is ubiquitous in living organisms and is of great significance in metabolism as a cofactor of various enzymes. Methyltransferases(MTases), a major group of SAMdependent enzymes, catalyze methyl transfer from SAM to C, O, N, and S atoms in small-molecule secondary metabolites and macromolecules, including proteins and nucleic acids. MTases have long been a hot topic in biomedical research because of their crucial role in epigenetic regulation of macromolecules and biosynthesis of natural products with prolific pharmacological moieties. However, another group of SAM-dependent enzymes, sharing similar core domains with MTases, can catalyze nonmethylation reactions and have multiple functions. Herein, we mainly describe the nonmethylation reactions of SAMdependent enzymes in biosynthesis. First, we compare the structural and mechanistic similarities and distinctions between SAM-dependent MTases and the non-methylating SAM-dependent enzymes. Second,we summarize the reactions catalyzed by these enzymes and explore the mechanisms. Finally, we discuss the structural conservation and catalytical diversity of class I-like non-methylating SAM-dependent enzymes and propose a possibility in enzymes evolution, suggesting future perspectives for enzymemediated chemistry and biotechnology, which will help the development of new methods for drug synthesis.

关键词： SAM-dependent enzyme Catalytic mechanism Biocatalysis Nonmethylation reaction Methyltransferase

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Epigenetic regulation of macrophages: from homeostasis maintenance to host defense

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Cellular & Molecular Immunology 2020年第1期17卷 36-49页

作者： Siyuan Chen Jing Yang Yuquan Wei Xiawei wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityNo.17Block 3Southern Renmin Road610041 ChengduSichuanPR China

Macrophages are crucial members of the innate immune response and important regulators.The differentiation and activation of macrophages require the timely regulation of gene expression,which depends on the interaction of a variety of factors,including transcription factors and epigenetic modifications.Epigenetic changes also give macrophages the ability to switch rapidly between cellular programs,indicating the ability of epigenetic mechanisms to affect phenotype plasticity.In this review,we focus on key epigenetic events associated with macrophage fate,highlighting events related to the maintenance of tissue homeostasis,responses to different stimuli and the formation of innate immune memory.Further understanding of the epigenetic regulation of macrophages will be helpful for maintaining tissue integrity,preventing chronic inflammatory diseases and developing therapies to enhance host defense.

关键词： Macrophage Epigenetics Polarization Immune memory

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Nanoparticles targeting tumor-associated macrophages:A novel anti-tumor therapy

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Nano Research 2022年第3期15卷 2177-2195页

作者： Siyuan Chen Furong Qin Manni Wang Yuquan Wei Zhiyong Qian Xiawei wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

The immunosuppressive tumor microenvironment(TME)is crucial in the occurrence of tumorigenesis,metastasis,and drug resistance.Among all stromal cells,tumor-associated macrophages(TAMs)are recognized as vital components causing the TME to be favorable for cancer cells and are also main targets in cancer immunotherapy.To date,nanoparticle(NP)-based drug delivery systems,as new technology platforms,have exhibited considerable advantages,such as targeted drug delivery at tumor sites,enhanced drug transport efficiency,and controllable drug release profiles,which provide new approaches for cancer therapy.Regarding TAM-targeting nanoparticles,various therapeutic strategies have been developed by varying their design,namely,by blocking TAM recruitment,promoting TAM transformation,and directly diminishing existing TAMs.In the current review,we provide a brief overview of the role of TAMs in the tumor microenvironment and their functions and highlight strategies for TAM targeting.Moreover,the applications of nanoparticles in targeting TAMs to improve cancer therapeutic efficiency are summarized.

关键词： tumors immunotherapy tumor-associated macrophages nanoparticles

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The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis

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Journal of Molecular Cell Biology 2021年第1期13卷 3-14页

作者： Lu Li An Tong Qiangsheng Zhang Yuquan Wei Xiawei wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer CenterNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China Department of Gynecology and Obstetrics Development and Related Disease of Women and Children Key Laboratory of Sichuan ProvinceKey Laboratory of Birth Defects and Related Diseases of Women and ChildrenMinistry of EducationWest China Second Hospitaland State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Necrosis,a type of unwanted and passive cell demise,usually occurs under the excessive external stress and is considered to be unregulated.However,under some special conditions such as caspase inhibition,necrosis is regulable in a well-orchestrated way.The term'regulated necrosis'has been proposed to describe such programed necrosis.Recently,several forms of necrosis,including necroptosis,pyroptosis,ferroptosis,parthanatos,oxytosis,NETosis,and Na^(+)/K^(+)ATPasimediated necrosis,have been identified,and some crucial regulators governing regulated necrosis have also been discovered.Mixed lineage kinase domain-like pseudokinase(MLKL),a core regulator in necroptosis,acts as an executioner in response to ligands of death receptor family.Its activation requires the receptor-interacting protein kinases,RIP1 and RIP3.However,MLKL is only involved in necroptosis,i.e.MLKL is dispensable for necrosis.Therefore,this review is aimed at summarizing the molecular mechanisms of MLKLdependent and MLKL-independent necrosis.

关键词： MLKL necrosis necroptosis mechanism diseases

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A new and promising application of gene editing: CRISPR-controlled smart materials for tissue engineering,bioelectronics, and diagnostics

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Science China(Life Sciences) 2019年第11期62卷 1547-1549页

作者： weiqi Hong Mengyuan Huang Yuquan Wei Xiawei wei Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan University

A recent study published in the journal Science by Collins et al.proposed a programmable clustered regularly interspaced short palindromic repeats(CRISPR)-responsive smart material containing the CRISPR-associated nuclease,Casl2a,and hydrogels containing DNA to deliver biological information via changes in material properties(English et al.,2019).

关键词： CRISPR smart journal

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