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信号转导与靶向治疗（英文）
信号转导与靶向治疗（英文）
信号转导与靶向治疗（英文）/Journal Signal Transduction and Targeted TherapyCSTPCDSCI
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    RNA modifications in cellular metabolism:implications for metabolism-targeted therapy and immunotherapy

    Wei-Wei LiuSi-Qing ZhengTian LiYun-Fei Fei...
    1565-1594页
    查看更多>>摘要：Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells.Relevant studies have been constantly making inroads in our understanding of pathophysiology,and inspiring development of therapeutics.As a crucial component of epigenetics at post-transcription level,RNA modification significantly determines RNA fates,further affecting various biological processes and cellular phenotypes.To be noted,immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts.In this review,we characterize the distribution features,modifying mechanisms and biological functions of 8 RNA modifications,including N6-methyladenosine(m6A),N6,2'-O-dimethyladenosine(m6Am),N1-methyladenosine(m1 A),5-methylcytosine(m5C),N4-acetylcytosine(ac4C),N7-methylguanosine(m7G),Pseudouridine(ψ),adenosine-to-inosine(A-to-I)editing,which are relatively the most studied types.Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described,categorized as glucose,lipid,amino acid,and mitochondrial metabolism.And we highlight the regulation of RNA modifications on immunometabolism,further influencing immune responses.Above all,we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy,progression of RNA modification-targeted agents,and its potential in RNA-targeted therapeutics.Eventually,we give legitimate perspectives for future researches in this field from methodological requirements,mechanistic insights,to therapeutic applications.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    The two sides of chromosomal instability:drivers and brakes in cancer

    Rendy HoseaSharon HillarySumera NaqviShourong Wu...
    1595-1624页
    查看更多>>摘要：Chromosomal instability(CIN)is a hallmark of cancer and is associated with tumor cell malignancy.CIN triggers a chain reaction in cells leading to chromosomal abnormalities,including deviations from the normal chromosome number or structural changes in chromosomes.CIN arises from errors in DNA replication and chromosome segregation during cell division,leading to the formation of cells with abnormal number and/or structure of chromosomes.Errors in DNA replication result from abnormal replication licensing as well as replication stress,such as double-strand breaks and stalled replication forks;meanwhile,errors in chromosome segregation stem from defects in chromosome segregation machinery,including centrosome amplification,erroneous microtubule-kinetochore attachments,spindle assembly checkpoint,or defective sister chromatids cohesion.In normal cells,CIN is deleterious and is associated with DNA damage,proteotoxic stress,metabolic alteration,cell cycle arrest,and senescence.Paradoxically,despite these negative consequences,CIN is one of the hallmarks of cancer found in over 90％of solid tumors and in blood cancers.Furthermore,CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity,thereby facilitating adaptive resistance to therapies;however,excessive CIN could induce tumor cells death,leading to the"just-right"model for CIN in tumors.Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments.This review provides an overview of causes and consequences of CIN,as well as the paradox of CIN,a phenomenon that continues to perplex researchers.Finally,this review explores the potential of CIN-based anti-tumor therapy.
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    • NETL
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    Contactin-associated protein-like 2(CNTNAP2)mutations impair the essential α-secretase cleavages,leading to autism-like phenotypes

    Qing ZhangMengen XingZhengkai BaoLu Xu...
    1625-1636页
    查看更多>>摘要：Mutations in the Contactin-associated protein-like 2(CNTNAP2)gene are associated with autism spectrum disorder(ASD),and ectodomain shedding of the CNTNAP2 protein plays a role in its function.However,key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown,and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive.In this report we showed that CNTNAP2 undergoes sequential cleavages by furin,ADAM 10/17-dependent a-secretase and presenilin-dependent γ-secretase.We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue 179 and L96,and the main α-cleavage product C79 by ADAM10 is required for the subsequent γ-secretase cleavage to generate CNTNAP2 intracellular domain(CICD).ASD-associated CNTNAP2 mutations impair the α-cleavage to generate C79,and the inhibition leads to ASD-like repetitive and social behavior abnormalities in the Cntnap2-I1254T knock-in mice.Finally,exogenous expression of C79 improves autism-like phenotypes in the Cntnap2-I1254T knock-in and Cntnap2-/- knockout mice.This data demonstrates that the α-secretase is essential for CNTNAP2 processing and its function.Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis,and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis

    Yuanliang YanShangjun ZhouXi ChenQiaoli Yi...
    1637-1650页
    查看更多>>摘要：Temozolomide(TMZ)represents a standard-of-care chemotherapeutic agent in glioblastoma(GBM).However,the development of drug resistance constitutes a significant hurdle in the treatment of malignant glioma.Although specific innovative approaches,such as immunotherapy,have shown favorable clinical outcomes,the inherent invasiveness of most gliomas continues to make them challenging to treat.Consequently,there is an urgent need to identify effective therapeutic targets for gliomas to overcome chemoresistance and facilitate drug development.This investigation used mass spectrometry to examine the proteomic profiles of six pairs of GBM patients who underwent standard-of-care treatment and surgery for both primary and recurrent tumors.A total of 648 proteins exhibiting significant differential expression were identified.Gene Set Enrichment Analysis(GSEA)unveiled notable alterations in pathways related to METABOLISM_OF_LIPIDS and BIOLOGICAL_OXIDATIONS between the primary and recurrent groups.Validation through glioma tissue arrays and the Xiangya cohort confirmed substantial upregulation of inositol 1,4,5-triphosphate(IP3)kinase B(ITPKB)in the recurrence group,correlating with poor survival in glioma patients.In TMZ-resistant cells,the depletion of ITPKB led to an increase in reactive oxygen species(ROS)related to NADPH oxidase(NOX)activity and restored cell sensitivity to TMZ.Mechanistically,the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent GBM samples accounted for the weakened ITPKB ubiquitination.This,in turn,elevated ITPKB stability and impaired ROS production.Furthermore,ITPKB depletion or the ITPKB inhibitor GNF362 effectively overcome TMZ chemoresistance in a glioma xenograft mouse model.These findings reveal a novel mechanism underlying TMZ resistance and propose ITPKB as a promising therapeutic target for TMZ-resistant GBM.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Structure-based design of pan-coronavirus inhibitors targeting host cathepsin L and calpain-1

    Xiong XieQiaoshuai LanJinyi ZhaoSulin Zhang...
    1651-1664页
    查看更多>>摘要：Respiratory disease caused by coronavirus infection remains a global health crisis.Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available,their efficacy on emerging coronaviruses in the future,including SARS-CoV-2 variants,might be compromised.Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses.Cathepsin L(CTSL)and calpain-1(CAPN1)are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response.Here,two peptidomimetic α-ketoamide compounds,14a and 14b,were identified as potent dual target inhibitors against CTSL and CAPN1.The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1.Both showed potent and broad-spectrum anticoronaviral activities in vitro,and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern(VOCs)with EC50 values ranging from 0.80 to 161.7 nM in various cells.Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance.Moreover,14a and 14b exhibited good oral pharmacokinetic properties in mice,rats and dogs,and favorable safety in mice.In addition,both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model.And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60％.Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia.Taken together,these results suggested that 14a and 14b are promising drug candidates,providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab for first-line treatment in advanced natural killer T cell lymphoma

    Jie XiongShu ChengXiao GaoShan-He Yu...
    1665-1674页
    查看更多>>摘要：Natural killer T cell lymphoma(NKTCL)is highly aggressive,with advanced stage patients poorly responding to intensive chemotherapy.To explore effective and safe treatment for newly diagnosed advanced stage NKTCL,we conducted a phase Ⅱ study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab(NCT04096690).Twenty-two patients with a median age of 51 years(range,24-74)were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days,followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days.The complete response and overall response rate after induction treatment were 59％(95％CI,43-79％)and 68％(95％CI,47-84％),respectively.With a median follow-up of 30 months,the 2 year progression-free and overall survival rates were 68％(95％CI,45-83％)and 86％(95％CI,63-95％),respectively.The most frequently grade 3/4 adverse events were neutropenia(32％,n=7)and hypofibrinogenemia(18％,n=4),which were manageable and led to no discontinuation of treatment.Tumor proportion score of PD-L1,peripheral blood high-density lipoprotein cholesterol,and apolipoprotein A-I correlated with good response,while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment.In conclusion,the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed,advanced stage NKTCL.Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance,providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer

    Lei MaChong ChenChunxing ZhaoTong Li...
    1675-1689页
    查看更多>>摘要：Despite the successful application of immune checkpoint therapy,no response or recurrence is typical in lung cancer.Cancer stem cells(CSCs)have been identified as a crucial player in immunotherapy-related resistance.Ferroptosis,a form of cell death driven by iron-dependent lipid peroxidation,is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with immunotherapy.Metabolic adaption of CSCs drives tumor resistance,yet the mechanisms of their ferroptosis defense in tumor immune evasion remain elusive.Here,through metabolomics,transcriptomics,a lung epithelial-specific Cpt1a-knockout mouse model,and clinical analysis,we demonstrate that CPT1A,a key rate-limiting enzyme of fatty acid oxidation,acts with L-carnitine,derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8+T cells inactivation in lung cancer.Mechanistically,CPT1A restrains ubiquitination and degradation of c-Myc,while c-Myc transcriptionally activates CPT1A expression.The CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating,thereby suppressing ferroptosis in CSCs.Significantly,targeting CPT1A enhances immune checkpoint blockade-induced anti-tumor immunity and tumoral ferroptosis in tumor-bearing mice.The results illustrate the potential of a mechanism-guided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CSCs to improve the efficacy of lung cancer immunotherapy.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis

    Yan FuKeyu ShenHao WangShun Wang...
    1690-1705页
    查看更多>>摘要：Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis.Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment.However,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown.Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that ICC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes ICC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted ICC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca2+-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKⅡ).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC progression.KN93,a small-molecule inhibitor of CAMKⅡ,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells.Above all,Acetylcholine/CHRNA5 axis increased the expression of β-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKⅡ/GSK3β signaling,and the CAMKⅡ inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Tet methylcytosine dioxygenase 2(TET2)deficiency elicits EGFR-TKI(tyrosine kinase inhibitors)resistance in non-small cell lung cancer

    Jian ZhangKejia ZhaoWenjing ZhouRan Kang...
    1706-1720页
    查看更多>>摘要：Despite epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKI)have shown remarkable efficacy in patients with EGFR-mutant non-small cell lung cancer(NSCLC),acquired resistance inevitably develops,limiting clinical efficacy.We found that TET2 was poly-ubiquitinated by E3 ligase CUL7FBXW11 and degraded in EGFR-TKI resistant NSCLC cells.Genetic perturbation of TET2 rendered parental cells more tolerant to TKI treatment.TET2 was stabilized by MEK1 phosphorylation at Ser 1107,while MEK1 inactivation promoted its proteasome degradation by enhancing the recruitment of CUL7FBXW11.Loss of TET2 resulted in the upregulation of TNF/NF-κB signaling that confers the EGFR-TKI resistance.Genetic or pharmacological inhibition of NF-κB attenuate the TKI resistance both in vitro and in vivo.Our findings exemplified how a cell growth controlling kinase MEK1 leveraged the epigenetic homeostasis by regulating TET2,and demonstrated an alternative path of non-mutational acquired EGFR-TKI resistance modulated by TET2 deficiency.Therefore,combined strategy exploiting EGFR-TKI and inhibitors of TET2/NF-κB axis holds therapeutic potential for treating NSCLC patients who suffered from this resistance.
      原文链接:
    • NETL
    • NSTL
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    Efficacy and safety of PD-1 blockade plus long-course chemoradiotherapy in locally advanced rectal cancer(NECTAR):a multi-center phase 2 study

    Zhengyang YangJiale GaoJianyong ZhengJiagang Han...
    1721-1729页
    查看更多>>摘要：Adding PD-1 blockade in the neoadjuvant regimens for locally advanced rectal cancer(LARC)patients with microsatellite stable(MSS)/mismatch repair-proficient(pMMR)tumors is an attractive,but debatable strategy.This phase 2,multicenter,prospective,single-arm study enrolled patients from 6 centers from June 2021 to November 2022.Locally advanced rectal cancer(LARC,cT3-4aN0M0 and cT1-4aN1-2M0)patients aged ≥18 years with the distance from distal border of tumor to anal verge ≤10 cm(identified by Magnetic Resonance Imaging)were qualified for inclusion.The patients received long-course radiotherapy(50 Gy/25 fractions,2 Gy/fraction,5 days/week)and three 21-day cycles capecitabine(850-1000 mg/m2,bid,po,day1-14)and three 21-day cycles tislelizumab(200 mg,iv.gtt,day8)as neoadjuvant.Total mesorectal excision(TME)was 6-12 weeks after the end of radiotherapy to achieve radical resection.A total of 50 patients were enrolled in this study.The pathological complete response rate was 40.0％[20/50,95％confidence interval(CI):27.61-53.82％],while 15(30.0％,95％CI:19.1-43.75％),9(18.0％,95％CI:9.77-30.8％),2(4.0％,95％CI:1.10-13.46％)patients respectively achieved grade 1,2,and 3 tumor regression.Treatment-related adverse events(TRAEs)occurred in 28(56.0％)LARC patients,including 26(52.0％)with grade Ⅰ-Ⅱ and 2(4.0％)with grade Ⅲ(1 with grade 3 immune-related colitis and 1 with grade 3 rash).PD-1 blockade plus long-course chemoradiotherapy(CRT)showed promising therapeutic effects according to pathological complete response rate and is well-tolerated in LARC patients.A larger randomized controlled study is desired to further validate the above findings.
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    • NETL
    • NSTL
    • 万方数据