Drug Resistance Updates最新文献

{"title":"The novel strategy to overcome the drug-resistant lung cancer: Dual targeting delivery of PROTAC to inhibit cancer-associated fibroblasts and lung cancer cells","authors":"Lingmin Zhang ,&nbsp;Linlong He ,&nbsp;Yinshan Lin ,&nbsp;Juyan Wei ,&nbsp;Shiqi Tang ,&nbsp;Xueping Lei ,&nbsp;Xufeng Lin ,&nbsp;Dazhi Zhou ,&nbsp;Liwu Fu ,&nbsp;Yuehua Li ,&nbsp;Juyun He ,&nbsp;Lu Liang ,&nbsp;Xi-Yong Yu","doi":"10.1016/j.drup.2025.101316","DOIUrl":"10.1016/j.drup.2025.101316","url":null,"abstract":"<div><div>Current pharmacotherapy on the fatal lung cancer is often limited by the development of drug resistance, which significantly contributes to treatment failure. The drug resistance in cancer is associated with tumor microenvironment (TME), particularly with cancer-associated fibroblasts (CAFs). However, the present approaches show little progress in the eliminating lung cancer cells and reversing the TME synergistically. The emergence of nanomedicine offers promising strategies to overcome this challenge. In this study, we developed a proteolysis-targeting chimeras (PROTAC)-based nanodrug, designed to eliminate both lung cancer cells and CAFs, thereby amplifying the therapeutic effects. This nanodrug was constructed by loading dBET6 with US Food and Drug Administration (FDA) approved polymer Poly(lactic-co-glycolic acid) (PLGA), and further camouflaged with the hybrid membranes derived from platelet and lung cancer cells (PLMPD). PLMPD demonstrated excellent dual-targeting capabilities to both lung cancer cells and CAFs, leading to significant apoptosis in both cell types in vitro. We also found that PLMPD could inhibited the growth of Osimertinib-resistant cells. In vivo studies revealed that PLMPD enhanced tumor targeting, effectively inhibited tumor growth, and reversed the tumor-promoting TME in the lung cancer xenograft models. These findings underscore the potential of PLMPD as a promising PROTAC-based nanodrug for lung cancer therapy, offering a new avenue for overcoming drug resistance and improving treatment outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101316"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363515","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":"Integration of blaOXA-48 into a Col156 plasmid drove a carbapenem-resistant Escherichia coli ST131 outbreak in New Zealand: Global genomic evidence for the gene’s multilayered dissemination","authors":"Rhys T. White ,&nbsp;Craig N. Thornley ,&nbsp;Max Bloomfield ,&nbsp;Kristin Dyet ,&nbsp;Juliet Elvy ,&nbsp;Hermes Perez ,&nbsp;Allan Hardaker ,&nbsp;Michael Harrington ,&nbsp;Simon Jackson ,&nbsp;Matthew Kelly ,&nbsp;Loushy Mangalasseril ,&nbsp;Annette Nesdale ,&nbsp;Xiaoyun Ren ,&nbsp;Jenny Szeto ,&nbsp;Claire Underwood ,&nbsp;David Winter ,&nbsp;Rosemary Woodhouse ,&nbsp;Zuyu Yang","doi":"10.1016/j.drup.2025.101327","DOIUrl":"10.1016/j.drup.2025.101327","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the genetic diversity in OXA-48-producing <em>Escherichia coli</em> ST131 in a New Zealand community outbreak, and to characterize the mobile genetic elements carrying <em>bla</em>_OXA-48, with emphasis on the gene’s global dissemination.</div></div><div><h3>Methods</h3><div>Forty outbreak isolates underwent short-read sequencing; 36 also underwent long-read sequencing. Bayesian phylogenetics reconstructed the emergence and spread of the outbreak. A pangenome graph of 543 Col156 plasmids and 806 global <em>bla</em>_OXA-48-positive contigs were analyzed to assess structural diversity, mobility, and global distribution.</div></div><div><h3>Results</h3><div>The outbreak clone likely emerged circa 2017, following a single introduction into New Zealand after acquiring <em>bla</em>_OXA-48 on a 7872 bp Col156 plasmid. It shares ancestry (circa 2009) with Southeast Asian <em>E. coli</em> ST131 genomes. Long-read sequencing and pangenome graph analyses identified a single IS<em>1</em>-mediated transposition of <em>bla</em>_OXA-48 into a Col156 plasmid backbone, observed across species and continents. Globally, <em>bla</em>_OXA-48 is present in diverse plasmid contexts and insertion sequence arrangements and is widely distributed among Enterobacterales.</div></div><div><h3>Conclusions</h3><div>This is the first high-resolution genomic reconstruction of a community-associated <em>bla</em>_OXA-48 outbreak, identifying a compact Col156 plasmid as a key vector driving carbapenem resistance. Our findings demonstrate the value of complete genome assemblies and pangenome graph analyses in resolving the structural and evolutionary dynamics of antimicrobial resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101327"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559712","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":"The role of tumor microenvironment and signaling pathways in regulating breast cancer stem cells: Implications for therapy resistance and tumor recurrence","authors":"Hongbo Zhang ,&nbsp;Yue Sun ,&nbsp;Rui Liu ,&nbsp;Hayam Hamdy ,&nbsp;Zhi Shi ,&nbsp;Dewei Jiang ,&nbsp;Jianwei Sun","doi":"10.1016/j.drup.2025.101315","DOIUrl":"10.1016/j.drup.2025.101315","url":null,"abstract":"<div><div>Breast cancer stem cells (BCSCs) are recognized as a critical subpopulation involved in cancer recurrence and metastasis, as they are capable of self-renewal and differentiate into various cell types. BCSCs play significant roles in tumor progression, being regulated by key signaling pathways such as Notch, PI3K/AKT/mTOR, and Hedgehog, and their interactions with the tumor microenvironment, which affect tumor growth and resistance to therapeutics. This review focuses on the surface markers of BCSCs, their roles in recurrence and metastasis, and the key signaling pathways. It also discusses the recent progress in understanding how BCSCs contribute to drug resistance and explores potential therapeutic strategies targeting these cells and their microenvironment to improve clinical outcomes and prevent relapse.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101315"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314883","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":"Gamma-synuclein drives bevacizumab resistance in colorectal cancer via VEGFR2 activation and angiogenesis","authors":"Caiyun Liu ,&nbsp;Lin Meng ,&nbsp;Lixin Wang ,&nbsp;Bin Dong ,&nbsp;Like Qu ,&nbsp;Chuanke Zhao ,&nbsp;Chengchao Shou","doi":"10.1016/j.drup.2025.101299","DOIUrl":"10.1016/j.drup.2025.101299","url":null,"abstract":"<div><h3>Background</h3><div>Resistance to Bevacizumab (Bev) remains a major obstacle in colorectal cancer (CRC) treatment. Gamma-synuclein (SNCG), overexpressed in tumor vasculature and cancer cells, is investigated here for its role in Bev resistance and therapeutic potential.</div></div><div><h3>Methods</h3><div>Using isogenic CRC models with SNCG overexpression or knockout, we assessed SNCG's impact on Bev response in vitro and in vivo. The therapeutic efficacy of combining Bev with an anti-SNCG monoclonal antibody (42#) was evaluated in Bev-resistant models. Mechanistic studies, including ELISA, Western blot, surface plasmon resonance (SPR), and molecular docking, explored interactions between SNCG, VEGF, and VEGFR2.</div></div><div><h3>Results</h3><div>SNCG overexpression reduced Bev sensitivity by impairing the inhibition of migration, invasion, and spheroid formation, whereas SNCG knockout enhanced therapeutic response. Molecular docking revealed that SNCG binds VEGFR2 at an allosteric site, forming a stable ternary complex (SNCG-VEGF-VEGFR2) with enhanced hydrogen bonding, which sustained VEGFR2 phosphorylation and angiogenesis. In vivo, SNCG-overexpressing tumors showed reduced responsiveness to Bev (42.8 % inhibition vs. 64.3 % in controls, <em>p</em> &lt; 0.05), while SNCG-deficient tumors exhibited a 3.2-fold increase in sensitivity. Combining Bev with 42# synergistically suppressed tumor growth (0.70 ± 0.36 g vs. 1.55 ± 0.41 g, <em>p</em> = 0.003), reduced metastatic burden (0.29 ± 0.23 g vs. 0.97 ± 0.42 g, <em>p</em> = 0.006), and extended median survival (86.8 vs. 69.8 days, <em>p</em> = 0.033) in Bev-resistant models.</div></div><div><h3>Conclusions</h3><div>SNCG drives Bev resistance in CRC by forming a ternary complex with VEGF and VEGFR2, enhancing VEGFR2 signaling and angiogenesis. Dual targeting of VEGF and SNCG represents a promising therapeutic strategy to overcome Bev resistance, with the potential to improve outcomes in CRC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101299"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145050623","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":"Peptide nanonet trapping suppresses bacterial motility and delays antibiotic resistance emergence","authors":"Jian Xu ,&nbsp;Nhan Dai Thien Tram ,&nbsp;Peiyan Yu,&nbsp;Dhanya Mahalakshmi Murali,&nbsp;Wei Meng Chen,&nbsp;Samantha Jinglin Yang ,&nbsp;Pui Lai Rachel Ee","doi":"10.1016/j.drup.2025.101320","DOIUrl":"10.1016/j.drup.2025.101320","url":null,"abstract":"<div><h3>Aims</h3><div>In the presence of antibiotics, motile bacteria can navigate chemical gradients for adaptation and survival. Antimicrobial peptides (AMPs) have been widely explored as adjuvant to improve the activity potency of antibiotics, but mainly through the disruption of bacterial membranes. In this work, we investigated the impact of nanonet trapping using fibrillating peptides, a mechanistically unique sub-group of AMPs, on motility recovery of bacteria and their capacity to develop antibiotic resistance.</div></div><div><h3>Methods</h3><div>The ability of fibrillating AMPs to potentiate activity and delay resistance of antibiotics from diverse classes was evaluated against clinical isolates of Gram-negative pathogens. Using soft agar assay and live-tracking microscopy, shifts in the motility of the bacteria population subjected to different treatments were evaluated. To further elucidate the mechanism of action, the expression of major flagella-encoding genes was quantified and hypomotile bacteria strains were studied.</div></div><div><h3>Results</h3><div>At sub-inhibitory concentrations, fibrillating peptides not only displayed synergistic interactions, but also significantly delayed the emergence of resistance to antibiotics such as rifampicin for at least 18 days. The peptide-antibiotic synergy profiles were lost after prolonged treatment with antibiotic monotherapy but preserved when co-administered with fibrillating peptides throughout the serial passage. The nanonet-forming peptides were shown to serve as a motility filter where the bacteria population gradually shifted towards homogeneous hypomotility associated with inferior survivability.</div></div><div><h3>Conclusions</h3><div>This work showcases the potential of AMPs as low-concentration adjuvants for extending the clinical lifespan of current antibiotics and highlights bacterial motility as an underexplored target for antibiotic development.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101320"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382791","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 delivery challenges of antimicrobial peptides for clinical translation: From nanocarriers to molecular modifications","authors":"Nan Gao,&nbsp;Jiaqi Sun,&nbsp;Xiang Li,&nbsp;Yuting Yao,&nbsp;Yujie Hu,&nbsp;Jiani Zhao,&nbsp;Anshan Shan,&nbsp;Jiajun Wang","doi":"10.1016/j.drup.2025.101289","DOIUrl":"10.1016/j.drup.2025.101289","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs) have emerged as a promising solution to combat multidrug-resistant (MDR) bacteria. Their unique mechanisms of action reduce the likelihood of resistance development. However, despite their potential, AMPs in clinical trials face significant challenges, including proteolytic degradation and short half-lives during systemic or oral administration. To address these limitations and enhance AMP stability and therapeutic efficacy, several key strategies have been explored. In this review, we summarize recent advances in AMP design, covering: 1) the delivery and formulation of AMPs, including metal-based, polymer-based, and lipid-based delivery systems, as well as the self-assembled nanotechnology of AMPs; 2) the internal modification of AMPs, including stereochemical modification, structural cyclization modification, and terminal modification. This review provides critical insights into AMP optimization, guides the development of future drug candidates, and highlights the interdisciplinary approaches required to accelerate clinical translation.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101289"},"PeriodicalIF":21.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809211","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":"Targeting DNA damage response pathways in tumor drug resistance: Mechanisms, clinical implications, and future directions","authors":"Hengzhou Zhu ,&nbsp;Yuanyang Tian ,&nbsp;Haoyan Chen ,&nbsp;Yiyang Qian ,&nbsp;Jiahui Li ,&nbsp;Dong Niu ,&nbsp;Wenyue Zhao ,&nbsp;Yulin Wu ,&nbsp;Xian Zhang ,&nbsp;Tao Tang ,&nbsp;Hu Li ,&nbsp;Yan-Fang Xian ,&nbsp;Dongdong Sun ,&nbsp;Chunhui Jin","doi":"10.1016/j.drup.2025.101287","DOIUrl":"10.1016/j.drup.2025.101287","url":null,"abstract":"<div><div>Targeting DNA damage response (DDR) pathways has become a promising strategy for overcoming tumor drug resistance, particularly in cancers with DNA repair defects. DDR pathways, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR), are essential for maintaining genomic stability. However, resistance to DDR-targeted therapies, such as PARP inhibitors, often arises due to tumor adaptation through various mechanisms. These include HR pathway restoration, mutations in DDR proteins, altered drug metabolism, and the activation of compensatory repair pathways. This review provides a comprehensive analysis of the molecular mechanisms underlying DDR resistance in tumors and explores the clinical implications of these mechanisms in the context of ongoing therapeutic strategies. We also discuss emerging approaches to overcome DDR resistance, including the development of novel DDR inhibitors, combination therapies, and precision medicine approaches based on biomarkers. Furthermore, we highlight future research directions, focusing on the use of advanced technologies, such as CRISPR screening, single-cell sequencing, and artificial intelligence, to uncover new targets and therapeutic strategies to combat DDR-related drug resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101287"},"PeriodicalIF":21.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809388","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":"Targeted therapy in acute myeloid leukemia: Resistance and overcoming strategy","authors":"Feifeng Song ,&nbsp;Sisi Lin ,&nbsp;Tong Xu ,&nbsp;Chang Yang ,&nbsp;Bold Sharavyn ,&nbsp;Hua Naranmandura ,&nbsp;Yiwen Zhang ,&nbsp;Ping Huang","doi":"10.1016/j.drup.2025.101286","DOIUrl":"10.1016/j.drup.2025.101286","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid blasts, leading to hematopoietic suppression and bone marrow failure. Advances in understanding the pathogenesis of AML have fueled the development of precision medicine approaches, with notable successes in targeting specific mutant proteins (e.g., FLT3, IDH1, IDH2), apoptotic regulators (e.g., BCL-2, MCL1), and cell-surface antigens (e.g., CD33, CD123, CD47). These targeted inhibitors exhibit moderate antileukemic activity as monotherapies and their clinical responses are often limited due to the emergence of drug resistance and disease relapse. Nevertheless, synergistic effects have been observed when these agents are combined with conventional chemotherapy or oncogenic pathway inhibitors. This review analyzes the current limitations of targeted therapies and explores multifaceted resistance drivers, encompassing on-target mutations, compensatory signaling pathway activation, drug-efflux mechanisms mediated by metabolic enzymes or transporters, intrinsic adaptive changes, and interactions with the tumor microenvironment. Corresponding therapeutic counterstrategies are also examined, such as mutation-specific molecular targeting, combinatorial suppression of alternative pathways, disruption of intrinsic adaptive responses, and immunotherapeutic approaches. These evolving interventions aim to overcome specific resistance mechanisms and reduce relapse rates. Future research integrating these strategies holds significant promise for addressing persistent challenges in AML management, ultimately advancing treatment paradigms and patient survival.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101286"},"PeriodicalIF":21.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781257","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":"Targeting CLK1/SRSF7 axis-dependent alternative splicing sensitizes pancreatic ductal adenocarcinoma to chemotherapy and immunotherapy","authors":"Chun Zhang ,&nbsp;Yinhao Chen ,&nbsp;Shuncang Zhu ,&nbsp;Zuwei Wang ,&nbsp;Hongyi Lin ,&nbsp;Jinpeng Lu ,&nbsp;Haoxiang Zhang ,&nbsp;Yueyi Weng ,&nbsp;Xiaoxiao Huang ,&nbsp;Ge Li ,&nbsp;Yongding Wu ,&nbsp;Zhiyuan Li ,&nbsp;Jianfei Hu ,&nbsp;Chengke Xie ,&nbsp;Jianlin Lai ,&nbsp;Yifeng Tian ,&nbsp;Chengyu Liao ,&nbsp;Shi Chen","doi":"10.1016/j.drup.2025.101292","DOIUrl":"10.1016/j.drup.2025.101292","url":null,"abstract":"<div><h3>Aim</h3><div>The persistently high mortality rate of pancreatic ductal adenocarcinoma (PDAC) is largely attributed to the acquired resistance to chemotherapy, particularly gemcitabine. This study aims to elucidate the underlying molecular mechanisms of gemcitabine resistance in PDAC, uncover additional pro-tumorigenic factors contributing to drug resistance, and develop more effective and safer targeted therapeutic strategies against this phenomenon.</div></div><div><h3>Methods</h3><div>Circular RNA (circRNA) sequencing was employed to identify differentially expressed circRNAs between chemo-sensitive and resistant tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) was utilized to uncover the RNA-binding proteins (RBPs) associated with circular RNA of alpha-1, 3-glucosyltransferase 8 (cALG8). Molecular biology techniques were applied to explore the biological functions and regulatory mechanisms of cALG8 in the context of gemcitabine resistance in PDAC. Single-cell sequencing was performed to reveal changes in the composition of tumor immune microenvironment of pancreatic cancer. Patient-Derived Organoid (PDO) and Patient-Derived Xenograft (PDX) were employed to further validate the molecular mechanisms. Finally, antisense oligonucleotides (ASOs) targeting cALG8 were developed for in vivo use, and their translational therapeutic potential was evaluated in mouse models.</div></div><div><h3>Results</h3><div>This study identified that cALG8, which is associated with alternative splicing, is highly expressed in gemcitabine-resistant PDAC cells. cALG8 regulates the alternative splicing complex, thereby promoting chemoresistance and immunosuppression in PDAC. Mechanistically, high level of cALG8 functions as a protein scaffold through its 34–85 nt and 109–160 nt regions, creating spatial conditions for CDC-like kinase 1 (CLK1) to phosphorylate serine/arginine-rich splicing factor 7 (SRSF7) at site 231S. This process facilitates the formation of the SRSF7-dependent ataxia-telangiectasia mutated (ATM) kinase variant, ATM203, enhancing the translational efficiency of ATM, and consequently promoting DNA damage repair and immune microenvironment remodeling in PDAC cells to counteract the effects of chemotherapeutic drugs. A cALG8-targeting ASO that disrupts the CLK1-SRSF7 interaction, when combined with gemcitabine and anti-programmed cell death protein (PD)-1 antibody, significantly reduced tumor burden in PDX model, validating its therapeutic translational value.</div></div><div><h3>Conclusion</h3><div>We demonstrated that the cALG8/CLK1/SRSF7 axis promotes ATM expression by enhancing the splicing of ATM203, thereby facilitating gemcitabine resistance and formation of an immunosuppressive microenvironment in PDAC. This insight aids in the development of drugs targeting chemotherapy resistance induced by DNA damage repair mechanisms in PDAC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101292"},"PeriodicalIF":21.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144866426","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":"Emerging role of sialylation in cancer therapy resistance: Mechanisms and therapeutic implications","authors":"Rebecca E. Farrell ,&nbsp;Kell A. Stelzer ,&nbsp;Guo-Jun Liu ,&nbsp;Danielle Skropeta","doi":"10.1016/j.drup.2025.101285","DOIUrl":"10.1016/j.drup.2025.101285","url":null,"abstract":"<div><div>Resistance to existing cancer therapies is a major factor contributing to cancer's persistence as a global health challenge. Abnormal sialylation patterns, commonly due to changes in the expression of sialyltransferases (STs) is a well-established property of tumour cells. There is a growing body of evidence to demonstrate that sialylation is involved in resistance to chemotherapy, targeted therapy, radiotherapy and immunotherapy through a variety of mechanisms that are still being unveiled. In this review, we summarise the reported correlations between aberrant sialylation and cancer therapy resistance, the underlying mechanisms discovered thus far, and progress made in targeting sialylation to enhance responsiveness to cancer treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101285"},"PeriodicalIF":21.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781258","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}