Drug Resistance Updates最新文献

{"title":"A quiescence-like/TGF-β1-specific CRISPRi screen reveals drug uptake transporters as secondary targets of kinase inhibitors in AML","authors":"Elahe Rahimian ,&nbsp;Masoud Koochak ,&nbsp;Sofia Traikov ,&nbsp;Michael Schroeder ,&nbsp;Silke Brilloff ,&nbsp;Silvia Schäfer ,&nbsp;Vida Kufrin ,&nbsp;Sandra Küchler ,&nbsp;Alexander Krüger ,&nbsp;Peter Mirtschink ,&nbsp;Gustavo Baretton ,&nbsp;Evelin Schröck ,&nbsp;Denis M. Schewe ,&nbsp;Claudia R. Ball ,&nbsp;Martin Bornhäuser ,&nbsp;Hanno Glimm ,&nbsp;Marius Bill ,&nbsp;Alexander A. Wurm","doi":"10.1016/j.drup.2025.101242","DOIUrl":"10.1016/j.drup.2025.101242","url":null,"abstract":"<div><div>Relapse in acute myeloid leukemia (AML) is driven by resistant subclones that survive chemotherapy. It is assumed that these resilient leukemic cells can modify their proliferative behavior by entering a quiescent-like state, similar to healthy hematopoietic stem cells (HSCs). These dormant cells can evade the effects of cytostatic drugs that primarily target actively dividing cells. Although quiescence has been extensively studied in healthy hematopoiesis and various solid cancers, its role in AML has remained unexplored.</div><div>In this study, we applied an HSC-derived quiescence-associated gene signature to an AML patient cohort and found it to be strongly correlated with poor prognosis and active TGF-β signaling. <em>In vitro</em> treatment with TGF-β1 induces a quiescence-like phenotype, resulting in a G0 shift and reduced sensitivity to cytarabine. To find potential therapeutic targets that prevent AML-associated quiescence and improve response to cytarabine, we conducted a comprehensive CRISPR interference (CRISPRi) screen combined with TGF-β1 stimulation. This approach identified TGFBR1 inhibitors, like vactosertib, as effective agents for preventing the G0 shift in AML cell models. However, pretreatment with vactosertib unexpectedly induced complete resistance to cytarabine. To elucidate the underlying mechanism, we performed a multi-faceted approach combining a second CRISPRi screen, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and <em>in silico</em> analysis. Our findings revealed that TGFBR1 inhibitors unintentionally target the nucleoside transporter <em>SLC29A1</em> (ENT1), leading to reduced intracellular cytarabine levels. Importantly, we found that this drug interaction is not unique to TGFBR1 inhibitors, but extends to other clinically significant kinase inhibitors, such as the FLT3 inhibitor midostaurin. These findings may have important implications for optimizing combination therapies in AML treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101242"},"PeriodicalIF":15.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143759039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting cTRIP12 counteracts ferroptosis resistance and augments sensitivity to immunotherapy in pancreatic cancer","authors":"Hongyi Lin ,&nbsp;Shuncang Zhu ,&nbsp;Yinhao Chen ,&nbsp;Jinpeng Lu ,&nbsp;Chengke Xie ,&nbsp;Chengyu Liao ,&nbsp;Xiaoxiao Huang ,&nbsp;Ge Li ,&nbsp;Yongding Wu ,&nbsp;Zhiyuan Li ,&nbsp;Jianfei Hu ,&nbsp;Xinquan Lin ,&nbsp;Yifeng Tian ,&nbsp;Qiaowei Li ,&nbsp;Zuwei Wang ,&nbsp;Shi Chen","doi":"10.1016/j.drup.2025.101240","DOIUrl":"10.1016/j.drup.2025.101240","url":null,"abstract":"<div><h3>Aims</h3><div>Current therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC) have limited efficacy in increasing patient survival rates, largely due to ferroptosis resistance and immunosuppression. The aim of this study is to identify molecular mechanisms associated with ferroptosis resistance and immunosuppression in PDAC tumour cells.</div></div><div><h3>Methods</h3><div>Circular RNA sequencing (circRNA-seq) was performed on clinical samples to identify potential circRNAs that mediate ferroptosis resistance. C11-BODIPY staining, FerroOrange staining, the glutathione ratio, malondialdehyde quantification, and transmission electron microscopy were employed to assess ferroptosis. RNA pulldown, mass spectrometry, RNA immunoprecipitation, and coimmunoprecipitation assays were conducted to investigate the molecular mechanisms involved. A HuNSG mouse xenograft tumour model was utilized to validate therapeutic agents.</div></div><div><h3>Results</h3><div>A circRNA derived from TRIP12 (cTRIP12) was identified in PDAC samples resistant to ferroptosis. cTRIP12 knockdown increased the sensitivity of PDAC cells to ferroptosis and immunotherapy. Subsequent mechanistic studies revealed that cTRIP12 specifically binds to the O-linked N-acetylglucosamine transferase (OGT) protein and increases intracellular O-GlcNAcylation levels, leading to increased protein levels of ferritin heavy chain (FTH) and PD-L1 in tumour cells. Notably, high cTRIP12 expression suppressed ferroptosis sensitivity and increased immune resistance in PDAC cells by functioning as a protein scaffold through its interaction with OGT and protein kinase R-like endoplasmic reticulum kinase (PERK). cTRIP12 inhibition induced ferroptosis in PDAC cells by reducing FTH and PD-L1 expression and synergistically increased the immunotherapy efficacy. In vivo animal experiments confirmed that the triple therapy consisting of GSK2656157, erastin, and anti-CTLA-4 effectively suppressed the progression of PDAC in tumours with high cTRIP12 expression.</div></div><div><h3>Conclusion</h3><div>We elucidated the molecular mechanisms underlying the simultaneous occurrence of ferroptosis resistance and immune suppression in PDAC patients. Our study provides a novel therapeutic strategy that could promote ferroptosis in tumour cells and increase immunotherapy efficacy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101240"},"PeriodicalIF":15.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting NAT10 attenuates homologous recombination via destabilizing DNA:RNA hybrids and overcomes PARP inhibitor resistance in cancers","authors":"Zhu Xu ,&nbsp;Mingming Zhu ,&nbsp;Longpo Geng ,&nbsp;Jun Zhang ,&nbsp;Jing Xia ,&nbsp;Qiang Wang ,&nbsp;Hongda An ,&nbsp;Anliang Xia ,&nbsp;Yuanyuan Yu ,&nbsp;Shihan Liu ,&nbsp;Junjie Tong ,&nbsp;Wei-Guo Zhu ,&nbsp;Yiyang Jiang ,&nbsp;Beicheng Sun","doi":"10.1016/j.drup.2025.101241","DOIUrl":"10.1016/j.drup.2025.101241","url":null,"abstract":"<div><h3>Aims</h3><div>RNA metabolism has been extensively studied in DNA double-strand break (DSB) repair. The RNA acetyltransferase N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification in DSB repair remains largely elusive. In this study, we aim to decipher the role for ac4C modification by NAT10 in DSB repair in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>Laser micro-irradiation and chromatin immunoprecipitation (ChIP) were used to assess the accumulation of ac4C modification and NAT10 at DSB sites. Cryo-electron microscopy (cryo-EM) was used to determine the structures of NAT10 in complex with its inhibitor, remodelin. Hepatocyte-specific deletion of NAT10 mouse models were adopted to detect the effects of NAT10 on HCC progression. Subcutaneous xenograft, human HCC organoid and patient-derived xenograft (PDX) model were exploited to determine the therapy efficiency of the combination of a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi) and remodelin.</div></div><div><h3>Results</h3><div>NAT10 promptly accumulates at DSB sites, where it executes ac4C modification on RNAs at DNA:RNA hybrids dependent on PARP1. This in turn enhances the stability of DNA:RNA hybrids and promotes homologous recombination (HR) repair. The ablation of NAT10 curtails HCC progression. Furthermore, the cryo-EM yields a remarkable 2.9 angstroms resolution structure of NAT10-remodelin, showcasing a C2 symmetric architecture. Remodelin treatment significantly enhanced the sensitivity of HCC cells to a PARPi and targeting NAT10 also restored sensitivity to a PARPi in ovarian and breast cancer cells that had developed resistance.</div></div><div><h3>Conclusion</h3><div>Our study elucidated the mechanism of NAT10-mediated ac4C modification in DSB repair, revealing that targeting NAT10 confers synthetic lethality to PARP inhibition in HCC. Our findings suggest that co-inhibition of NAT10 and PARP1 is an effective novel therapeutic strategy for patients with HCC and have the potential to overcome PARPi resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101241"},"PeriodicalIF":15.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143685059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Widespread antibiotic heterotolerance in bacteria remains undetected by resistance assays","authors":"Bram Van den Bergh ,&nbsp;Philip Ruelens ,&nbsp;Lieze Agten ,&nbsp;Laurence Van Moll ,&nbsp;Nele Geerts ,&nbsp;Laure Verstraete ,&nbsp;Sang Nguyen ,&nbsp;Linda De Vooght ,&nbsp;Natalie Verstraeten ,&nbsp;Paul Cos ,&nbsp;Jan Michiels","doi":"10.1016/j.drup.2025.101239","DOIUrl":"10.1016/j.drup.2025.101239","url":null,"abstract":"<div><div>Despite global efforts, antimicrobial resistance persists. Mechanisms like heterotolerance further undermine antibiotic effectiveness. Testing &gt; 1000 clinical strains revealed widespread heterotolerance largely missed by conventional MIC-based diagnostics. Since AMR alone does not predict treatment success, new tests and strategies incorporating tolerance data are urgently needed to significantly improve patient outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101239"},"PeriodicalIF":15.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD105 blockade restores osimertinib sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer","authors":"Manish Thiruvalluvan ,&nbsp;Sandrine Billet ,&nbsp;Zhenqiu Liu ,&nbsp;Joseph Lownik ,&nbsp;Barliz Waissengrin ,&nbsp;Hyoyoung Kim ,&nbsp;Anton L. Villamejor ,&nbsp;Larry Milshteyn ,&nbsp;Xiamo Li ,&nbsp;Matthew Gayhart ,&nbsp;Manuel Araña ,&nbsp;Kamya Sankar ,&nbsp;Edwin M. Posadas ,&nbsp;Jean Lopategui ,&nbsp;Sungyong You ,&nbsp;Karen L. Reckamp ,&nbsp;Neil A. Bhowmick","doi":"10.1016/j.drup.2025.101237","DOIUrl":"10.1016/j.drup.2025.101237","url":null,"abstract":"<div><h3>Aim</h3><div>To investigate the role of CD105 in mediating drug resistance to EGFR-targeted therapy in non-small cell lung cancer (NSCLC).</div></div><div><h3>Methods</h3><div>Imaging mass cytometry was conducted on 66 NSCLC tumors, 44 of which had EGFR mutations. We correlated clinical variables, including overall survival, with CD105 (endoglin) expression, a co-receptor for bone morphogenetic protein (BMP) signaling. Two osimertinib-resistant EGFR-mutant cell lines were developed to study the effects of EGFR and CD105 disruption. Single cell RNA sequencing of the isogenic parental and osimertinib resistant lines was performed. Additionally, ATAC sequencing and Single Cell ENergetIc metabolism by profiling Translation inHibition analysis (SCENITH) was used to assess promoter chromatin status and glycolytic state.</div></div><div><h3>Results</h3><div>We found a negative correlation between CD105 expression and overall survival in patients. Treatment with osimertinib or EGFR knockdown significantly elevated CD105 expression in EGFR-mutant cell lines. Single-cell RNA sequencing identified a subset of cells with heightened endothelial characteristics and altered pyrimidine metabolism, associated with osimertinib resistance. These cells exhibited a slow-cycling behavior, characterized by elevated chromatin condensation and reduced glycolysis. Combining osimertinib with carotuximab, a CD105 neutralizing antibody, significantly reduced the slow-cycling transcriptomic signature, increased chromatin accessibility, and restored glycolysis compared to osimertinib treatment alone. Mass spectrometry confirmed that carotuximab re-engaged EGFR signaling by coupling it with CD105. Consequently, carotuximab re-sensitized resistant tumors to osimertinib by increasing their mitotic index and ERK signaling in mouse models.</div></div><div><h3>Conclusion</h3><div>Carotuximab effectively reduced the slow-cycling cell population and restored osimertinib sensitivity, offering a promising strategy for managing refractory NSCLC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101237"},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the sulfur-containing amino acid-ROS axis in cancer chemotherapeutic drug resistance","authors":"Bingli Wu ,&nbsp;Yinwei Cheng ,&nbsp;Liyan Li ,&nbsp;Zepeng Du ,&nbsp;Qianlou Liu ,&nbsp;Xinyue Tan ,&nbsp;Xin Li ,&nbsp;Guozhi Zhao ,&nbsp;Enmin Li","doi":"10.1016/j.drup.2025.101238","DOIUrl":"10.1016/j.drup.2025.101238","url":null,"abstract":"<div><div>Chemotherapeutic drug resistance remains a major barrier to effective cancer treatment. Drug resistance could be driven in part by adaptive redox remodeling of cancer cells. Paradoxically, drug-resistant malignancies exhibit elevated reactive oxygen species (ROS), as well as amplified antioxidant defenses, which enable cancer cell survival under therapeutic stress. Central to this adaptation is glutathione (GSH), the predominant cellular antioxidant, whose synthesis relies on sulfur-containing amino acids (SAAs) – methionine and cysteine. This review delineates the metabolic interplay between methionine and cysteine in the transsulfuration pathway, highlighting their roles as precursors in GSH biosynthesis. We systematically summarize the key enzymes that drive GSH production and their contributions to resistance against platinum-based drugs and other chemotherapeutics. In addition to GSH synthesis, we summarize the roles of GSH antioxidant systems, including glutathione peroxidases (GPXs), peroxiredoxins (PRDXs), and thioredoxins (TRXs), which are critical in chemotherapeutic drug resistance through ROS scavenging. Recent advances reveal that targeting these enzymes, by pharmacologically inhibiting transsulfuration enzymes or disrupting GSH-dependent antioxidant cascades, can sensitize resistant cancer cells to ROS-mediated therapies. These findings not only clarify the mechanistic links between SAA metabolism and redox adaptation but also provide practical approaches to overcome chemotherapeutic drug resistance. By analyzing metabolic and redox vulnerabilities, this review highlights the therapeutic potential to restore chemosensitivity, offering new options in precision oncology medicine.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101238"},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143642743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming cancer therapy resistance: From drug innovation to therapeutics","authors":"Jin-Rui Wei ,&nbsp;Meng-Yi Lu ,&nbsp;Tian-Hua Wei ,&nbsp;Joshua S. Fleishman ,&nbsp;Hui Yu ,&nbsp;Xiao-Li Chen ,&nbsp;Xiang-Tu Kong ,&nbsp;Shan-Liang Sun ,&nbsp;Nian-Guang Li ,&nbsp;Ye Yang ,&nbsp;Hai-Wen Ni","doi":"10.1016/j.drup.2025.101229","DOIUrl":"10.1016/j.drup.2025.101229","url":null,"abstract":"<div><div>One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101229"},"PeriodicalIF":15.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging and senescence: Key players in brain tumor progression and drug resistance","authors":"Chao Zhang ,&nbsp;Neha ,&nbsp;Jiaqi Zhang ,&nbsp;Prashant ,&nbsp;Xiaodie Li ,&nbsp;Sarad Kumar Mishra ,&nbsp;Joshua Fleishman ,&nbsp;Suhel Parvez ,&nbsp;Saurabh Kumar Jha ,&nbsp;Min Huang","doi":"10.1016/j.drup.2025.101228","DOIUrl":"10.1016/j.drup.2025.101228","url":null,"abstract":"<div><div>Aging plays a critical role in the development, progression, and therapeutic challenges associated with brain tumors, particularly glioblastomas (GBM). As the population ages, the incidence of brain tumors, including GBM, increases, with aging emerging as a significant prognostic factor influencing survival outcomes. This review examines the molecular mechanisms linking aging and brain tumor progression, with a specific focus on glioblastomas. We explore how age-related genetic mutations, alterations in cellular pathways, and changes in the tumor microenvironment (TME) contribute to tumorigenesis and treatment resistance. Furthermore, we highlight the impact of key signaling pathways, such as the PI3K/AKT/mTOR, p53, and EGFR/PTEN, which are frequently dysregulated in both aging and brain tumors. Despite the growing recognition of aging as a critical factor in brain tumor biology, therapeutic strategies for elderly patients remain poorly defined, often due to underrepresentation in clinical trials and the complex interplay of comorbidities and treatment side effects. The review also discusses emerging therapeutic approaches, including targeted therapies and immunotherapies, which offer promise for improving treatment outcomes by addressing age-related molecular changes. Finally, we emphasize the importance of personalized treatment strategies and the need for further research to better understand the biological mechanisms underlying the aging-brain tumor relationship, ultimately aiming to enhance clinical management and patient quality of life.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101228"},"PeriodicalIF":15.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGFβ-activated Asporin interacts with STMN1 to promote prostate cancer docetaxel chemoresistance and metastasis by upregulating the Wnt/β-catenin signaling pathway","authors":"Shengdong Ge ,&nbsp;Jinpeng Cen ,&nbsp;Xiaofeng Liu ,&nbsp;Yaying Hong ,&nbsp;Yuting Tang ,&nbsp;Yuzhong Yu ,&nbsp;Haolin Li ,&nbsp;Tao Xie ,&nbsp;Chong Wang ,&nbsp;Maoping Cai ,&nbsp;Yang Qiu ,&nbsp;Xianzi Zeng ,&nbsp;Tianming Peng ,&nbsp;Qu Li ,&nbsp;Qianyi Li ,&nbsp;Xingcheng Wu ,&nbsp;Xian-Lu Song ,&nbsp;Shan-Chao Zhao","doi":"10.1016/j.drup.2025.101227","DOIUrl":"10.1016/j.drup.2025.101227","url":null,"abstract":"<div><h3>Aims</h3><div>Prostate cancer (PCa) remains a significant challenge in oncology due to high rates of drug resistance following standard treatment with docetaxel-based chemotherapy. Asporin (ASPN) has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. Studies indicated that abnormal activation of the Wnt/β-catenin signaling pathway is prevalent in PCa. This study investigated the important role of ASPN in regulating Wnt/β-catenin signaling pathway in docetaxel resistance and metastasis of PCa.</div></div><div><h3>Methods</h3><div>The impacts of ASPN on the docetaxel chemoresistance and metastasis of PCa cells were investigated in vitro and in vivo assays. Lastly, the underlying mechanism of ASPN was revealed by Western blot, protein immunocoprecipitation, Immunofluorescence, Immunohistochemical staining, liquid chromatography-mass spectrometry, and rescue experiments.</div></div><div><h3>Results</h3><div>In present study, we reported that ASPN is highly expressed in PCa cells and tissues. Functional and molecular analyses showed that ASPN is activated by TGFβ and interacts with STMN1. ASPN increases the expression of β-catenin and promotes its nuclear accumulation by mediating the activation of the Wnt/β-catenin signaling pathway, thereby enhancing the stemness and epithelial-mesenchymal transition (EMT) of PCa cells, ultimately facilitating the docetaxel resistance and metastasis of PCa cells.</div></div><div><h3>Conclusions</h3><div>Our findings identify ASPN as a novel upstream regulatory factor of Wnt/β-catenin signaling pathway, suggesting that targeting the ASPN/STMN1/β-catenin axis could be a promising strategy for PCa intervention.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101227"},"PeriodicalIF":15.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel insights into taxane pharmacology: An update on drug resistance mechanisms, immunomodulation and drug delivery strategies","authors":"Giovanni Luca Beretta ,&nbsp;Giuliana Cassinelli ,&nbsp;Giacomina Rossi ,&nbsp;Amalia Azzariti ,&nbsp;Iléana Corbeau ,&nbsp;Diego Tosi ,&nbsp;Paola Perego","doi":"10.1016/j.drup.2025.101223","DOIUrl":"10.1016/j.drup.2025.101223","url":null,"abstract":"<div><div>Taxanes are effective in several solid tumors. Paclitaxel, the main clinically available taxane, was approved in the early nineties, for the treatment of ovarian cancer and later on, together with the analogs docetaxel and cabazitaxel, for other malignancies. By interfering with microtubule function and impairing the separation of sister cells at mitosis, taxanes act as antimitotic agents, thereby counteracting the high proliferation rate of cancer cells. The action of taxanes goes beyond their antimitotic function because their main cellular targets, the microtubules, participate in multiple processes such as intracellular transport and cell shape maintenance. The clinical efficacy of taxanes is limited by the development of multiple resistance mechanisms. Among these, extracellular vesicles have emerged as new players. In addition, taxane metronomic schedules shows an impact on the tumor microenvironment reflected by antiangiogenic and immunomodulatory effects, an aspect of growing interest considering their inclusion in treatment regimens with immunotherapeutics. Preclinical studies have paved the bases for synergistic combinations of taxanes both with conventional and targeted agents. A variety of drug delivery strategies have provided novel opportunities to increase the drug activity. The ability of taxanes to orchestrate different cellular effects amenable to modulation suggests novel options to improve cures in lethal malignancies.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101223"},"PeriodicalIF":15.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143611106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}