癌症耐药(英文)最新文献

{"title":"Adaptive drug resistance in melanoma is characterised by lipidome remodelling while maintaining cell membrane biophysical properties.","authors":"Aurélie H Benfield, Reuben S E Young, Grégoire J B Philippe, Nicholas D Condon, Nicolau Barbosa Palma Filho, Helmut Schaider, Stephen J Blanksby, Sónia Troeira Henriques","doi":"10.20517/cdr.2026.54","DOIUrl":"10.20517/cdr.2026.54","url":null,"abstract":"<p><p><b>Aim:</b> Cancer drug resistance is driven by dynamic, systems-level adaptations, including cellular state transitions, epigenetic reprogramming, metabolic rewiring, and proteome remodelling. Lipid metabolic reprogramming is increasingly recognised as a contributor to resistance through alterations in the membrane composition and has been hypothesised to promote resistance by increasing membrane rigidity and limiting drug permeability. Here we tested this hypothesis in melanoma using a cell state-resolved multi-omics approach. <b>Methods:</b> We combined lipidomics, surface-resolved phospholipid profiling, live-cell biophysical measurements, and whole-cell proteomics to characterise plasma membrane composition and function across drug-naïve, drug-tolerant persister, and permanently drug-resistant states in BRAF^V600E metastatic melanoma cells treated with dabrafenib. <b>Results:</b> Lipidomic analyses revealed membrane remodelling, particularly in the drug-tolerant state, including altered fatty acid chain unsaturation, and increased cholesterol (Chol) and sphingomyelin levels. All cell states retained surface exposure of negatively charged phosphatidylserine and phosphatidylinositol. Despite compositional changes typically associated with membrane rigidification, plasma membrane fluidity and tension remain conserved across all resistance states. Proteomic analysis further revealed coordinated regulation of lipid metabolic pathways, including Chol homeostasis and sphingolipid turnover, indicating that lipid-metabolic adaptation supports survival under drug pressure without substantially altering membrane biophysical properties. <b>Conclusion:</b> These findings show that lipid metabolic rewiring supports drug tolerance while conserving core membrane features. By resolving resistance-associated changes across both molecular and biophysical layers, this study identifies shared plasma membrane features and vulnerabilities across heterogeneous melanoma cell populations, supporting the application of membrane-active therapeutic agents and of combination strategies targeting lipid-metabolic adaptations to delay or prevent resistance.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"35"},"PeriodicalIF":4.6,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13680111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149231316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PSMD14 as a translational target in cancer and beyond: from deubiquitination mechanisms to drug resistance and precision therapy.","authors":"Hongrui Liu, Liang Ma, Yixuan Wang, Yuheng Wang, Siyu Chen, Mingzhen Wang, Dingge Cao, Yi Chen, Wenzhe Si","doi":"10.20517/cdr.2026.80","DOIUrl":"10.20517/cdr.2026.80","url":null,"abstract":"<p><p>The deubiquitinase PSMD14 (also known as RPN11 or POH1), a critical component of the JAB1/MPN/Mov34 metalloenzyme family, has emerged as a pivotal regulator of protein homeostasis through its deubiquitinating activity. While preclinical studies have extensively characterized PSMD14-mediated stabilization of oncogenic substrates involved in cell cycle progression, programmed cell death, metastasis, metabolic reprogramming, and immune evasion, a translational gap remains between these mechanistic insights and clinical application. This review synthesizes current evidence demonstrating that PSMD14 drives therapeutic resistance across multiple malignancies, including resistance to cisplatin, oxaliplatin, temozolomide, anlotinib, tamoxifen, and bortezomib by deubiquitinating and stabilizing key effectors such as E2F1, ALK2, IMPDH2, estrogen receptor α, and proteasomal components. Furthermore, we highlight the prognostic value of PSMD14 as a biomarker for overall survival and recurrence prediction in hepatocellular carcinoma, pancreatic cancer, lung cancer, and other malignancies, along with its emerging role in non-tumor conditions such as glucocorticoid-induced osteoporosis and post-cardiac arrest neurological outcomes. We critically evaluate the therapeutic landscape of PSMD14 inhibitors, from natural products (thiolutin) and synthetic agents (Capzimin, O-phenanthroline) to next-generation dual-target inhibitors, and discuss the clinical barriers to translation, including off-target toxicity, patient stratification, and optimal combination strategies. By integrating mechanistic discovery with biomarker development and inhibitor optimization, this review aims to lay a foundation for the future development of PSMD14-targeted therapeutic strategies.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"34"},"PeriodicalIF":4.6,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resistance to third-generation EGFR TKIs - what can be expected from the fourth-generation?","authors":"Wolfram C M Dempke, Klaus Fenchel, Loretta Sullivan, Martin Reck","doi":"10.20517/cdr.2026.79","DOIUrl":"10.20517/cdr.2026.79","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors (TKIs) have significantly changed the treatment of non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations, and osimertinib is now established as first-line therapy for NSCLCs. Combination therapies (e.g., osimertininb plus chemotherapy; lazertinib plus amivantamab) have been shown to improve median progression-free survival (mPFS) and median overall survival (mOS) relative to monotherapy. However, due to several resistance mechanisms, patients experience disease progression following EGFR TKI treatment. On-target resistance mechanisms include additional mutations (e.g., C797S/G/N, L718Q, L844V, G724X). Within the heterogeneous group of off-target resistance mechanisms, human epidermal growth factor receptor 2 (HER2) amplifications, mesenchymal-epithelial transition factor (MET) alterations, oncogenic fusions (e.g., BRAF, FGFR, RET), histological changes, epithelial-mesenchymal transitions, and alterations of the RAS/MEK/ERK and the PI3K/AKT/mTOR signal transduction pathways are critical and can confer resistance to EGFR TKIs. Several drugs have been identified to inhibit these pathways, with some of them already approved for clinical use. Most fourth-generation EGFR TKIs are orally bioavailable and are mainly allosteric thiazole amide-based reversible inhibitors. Their activity results from selective binding to an allosteric site, which can alter the EGFR protein conformation, allowing them to bypass C797X. A recommendation for the optimal treatment strategy and sequence for NSCLC patients with acquired EGFR TKI-resistant tumours still cannot be given. An improved understanding of the underlying resistance mechanisms will help to pave the way for the development of innovative and highly specific drugs for the therapy of osimertinib-resistant NSCLCs. The putative clinical relevance of fourth-generation EGFR TKIs for NSCLC patients needs to be defined, and many development hurdles need to be cleared before victory can be declared.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"33"},"PeriodicalIF":4.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ST6GAL1 promotes cancer stem-like cell-associated paclitaxel resistance through the EGFR-mTOR-SOX2/BMI1 axis in non-small cell lung cancer.","authors":"Yuxi Yang, Binghui Liang, Weijie Hong, Sau Har Lee, Dongfang Tang, Shuxian Xie, Changtai Qin, Liu Shen, Zhumei Sun, Xiaofeng Yan, Hua Li, Xiaoling Wang, Xudong Hu, Tingjie Ye, Wei Zhang, Wei Xu","doi":"10.20517/cdr.2026.66","DOIUrl":"10.20517/cdr.2026.66","url":null,"abstract":"<p><p><b>Aim:</b> Despite the contribution of cancer stem-like cells (CSLCs) to acquired paclitaxel resistance in non-small cell lung cancer (NSCLC), the biomarkers and regulatory mechanisms sustaining their stemness under chemotherapy pressure remain poorly understood. This study aimed to identify the stemness-maintaining programs underlying CSLC-associated paclitaxel resistance. <b>Methods:</b> Paclitaxel-resistant NSCLC cell models were established. RNA-seq data from resistant spheres and adherent resistant cells were integrated with Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/gene set enrichment analysis and patient transcriptomic datasets to identify CSLC maintenance-associated candidate biomarkers. Inhibitors, sphere-forming assays, CD104^-CD166⁺CD49f^hi flow cytometry, reverse transcription quantitative polymerase chain reaction, western blotting, and ST6GAL1 knockdown or overexpression were used for functional and mechanistic validation. Sambucus nigra agglutinin lectin blotting was performed to assess epidermal growth factor receptor (EGFR) α2,6-sialylation. Clinical relevance was assessed using ST6GAL1 immunohistochemistry on 46 clinical lung tumor tissues. <b>Results:</b> Paclitaxel-resistant NSCLC cells exhibited enhanced sphere formation and CD104^-CD166⁺CD49f^hi expansion. N-glycosylation was activated in resistant spheres. A seven-gene N-glycosylation signature was identified as a CSLC-associated candidate biomarker in acquired paclitaxel resistance. Inhibiting N-glycosylation suppressed the EGFR-mTOR-SOX2/BMI1 axis, decreased CSLCs, and restored paclitaxel sensitivity. ST6GAL1 regulated EGFR α2,6-sialylation. ST6GAL1 depletion also decreased EGFR abundance, suppressed mTOR-SOX2/BMI1 signaling, and sensitized paclitaxel-resistant spheres to paclitaxel rather than adherent cells. ST6GAL1 expression, which was higher in tumors from patients who underwent chemotherapy, showed a trend toward poorer survival among chemotherapy-treated patients. The seven-gene signature was associated with shorter disease-free survival but not overall survival in lung cancer patients. <b>Conclusions:</b> ST6GAL1-mediated α2,6-sialylation of EGFR contributes to the maintenance of CSLC-associated paclitaxel resistance through mTOR-SOX2/BMI1 signaling. These findings identify ST6GAL1-dependent EGFR sialylation as a potential therapeutic target in CSLC-associated chemoresistance.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"32"},"PeriodicalIF":4.6,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149013249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bracing for the storm: emerging resistance mechanisms to KRAS inhibitors in pancreatic cancer and strategies to overcome them.","authors":"Marco Pagano Mariano, Enrica Sgarilli, Dirk Mijnlieff, Bonifiya Visuvasam, Andrea Blesio, Graziana Digiacomo, Andrea Cavazzoni, Manuela Ferracin, Elisa Giovannetti","doi":"10.20517/cdr.2026.52","DOIUrl":"10.20517/cdr.2026.52","url":null,"abstract":"<p><p>Oncogenic KRAS mutations are a defining feature of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal solid malignancies, characterized by poor responsiveness to chemotherapy. Recent clinical successes of direct KRAS inhibitors in other cancer types have renewed interest in KRAS-directed therapy for PDAC. However, early clinical experience has revealed often short-lived responses, highlighting the rapid emergence of resistance and the need to understand the mechanisms limiting durable benefit. This review summarizes current knowledge on molecular resistance to RAS-directed inhibitors in PDAC, organized into five categories: intrinsic resistance, KRAS-dependent mechanisms, KRAS-independent bypass signaling, downstream pathway reactivation, and tumor microenvironment (TME)-mediated resistance. Evidence from PDAC models is integrated with insights from other KRAS-driven malignancies, particularly non-small cell lung cancer, where direct KRAS inhibition has been studied extensively. Collectively, resistance appears to arise from layered adaptive processes rather than single alterations, including secondary <i>KRAS</i> mutations, receptor tyrosine kinase-driven bypass signaling, reactivation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, stromal-mediated protection, and reduced drug exposure. Notably, until recently, most evidence in PDAC has been indirect, while direct investigation of resistance mechanisms in KRAS-targeted settings has expanded rapidly only in recent years. Building on these advances, ongoing clinical trials increasingly explore rational combination strategies targeting upstream regulators, downstream effectors, and the TME. However, critical challenges persist, including patient selection, treatment sequencing, toxicity, and the lack of pharmacodynamic frameworks. Overcoming resistance will require mechanistically guided combinations, improved disease-specific models, and biomarker-driven adaptive strategies to ultimately achieve durable clinical benefits in PDAC.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"31"},"PeriodicalIF":4.6,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Divergent transcriptional programs and constrained metabolic states reveal selective metabolic dependencies in chemoresistant luminal breast cancer.","authors":"Melis Poyraz, Buse Sari, Jérôme Ambroise, Melanie Spears, Martin Michaelis, Jindrich Cinatl, Romain Boidot, Kristian Serafimov, Olivier Feron, François P Duhoux, Manon Desgres, Cyril Corbet","doi":"10.20517/cdr.2026.57","DOIUrl":"10.20517/cdr.2026.57","url":null,"abstract":"<p><p><b>Aim:</b> Resistance to neoadjuvant chemotherapy remains a major challenge in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC). Although anthracyclines and taxanes constitute the standard sequential regimen, the metabolic adaptations accompanying resistance to these agents remain poorly defined. We investigated whether chemoresistance is associated with shared or drug-specific metabolic alterations. <b>Methods:</b> Parental MCF-7 and ZR-75-1 cells and their anthracycline-, and taxane-resistant derivatives, were characterized through multi-omics, Seahorse-based metabolic flux, and pharmacological inhibition analyses, alongside validation in patient transcriptomic datasets. <b>Results:</b> Chemoresistant cells displayed reduced drug sensitivity and improved recovery following treatment withdrawal. Transcriptomic profiling revealed extensive yet largely distinct gene expression changes among resistant models, whereas metabolomics showed limited divergence. Functional studies demonstrated concurrent reductions in mitochondrial respiration and glycolytic capacity, indicating a low-bioenergetic phenotype without compensatory metabolic rewiring. Lipidomic changes were heterogeneous and model-dependent. Despite this overall metabolic constraint, spermidine and spermine levels were increased across all resistant models, whereas upregulation of the polyamine-related genes <i>ATP13A4</i> and <i>SAT1</i> was specific to anthracycline-resistant cells. Chemoresistant phenotypes conferred reduced sensitivity to mitochondrial inhibitors. In contrast, sensitivity to polyamine pathway inhibition varied across models. Clinical datasets corroborated key experimental features, showing increased ATP binding cassette subfamily B member 1 (<i>ABCB1</i>) expression and significant post-treatment suppression of oxidative phosphorylation and glycolysis signatures. Polyamine pathway enrichment trends were less uniform, reflecting clinical heterogeneity. <b>Conclusion:</b> Chemoresistance in HR+/HER2- BC is characterized by heterogeneous transcriptional remodeling but relative metabolic constraint. Clinical dataset validation confirms post-chemotherapy bioenergetic suppression, while polyamine alterations represent context-dependent adaptations rather than universal vulnerabilities.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"30"},"PeriodicalIF":4.6,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenylosuccinate lyase in pancreatic ductal adenocarcinoma chemoresistance: from purine metabolism to metabolic vulnerability.","authors":"Tung-Wei Hsu, Chih-Ming Su, Yen-Hao Su, Po-Hsiang Liao, Charupong Saengboonmee, Wan-Yu Wang, Hsin-An Chen","doi":"10.20517/cdr.2026.58","DOIUrl":"10.20517/cdr.2026.58","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human malignancies and is characterized by profound metabolic reprogramming and marked therapeutic resistance. Among the metabolic enzymes that sustain tumor fitness, adenylosuccinate lyase (ADSL) has emerged as a critical regulator of <i>de novo</i> purine biosynthesis with broader roles in oncogenic signaling, metabolic adaptation, and chemoresistance. ADSL catalyzes two key reactions in purine synthesis, contributing to adenylosuccinate-to-adenosine monophosphate (AMP) production, fumarate generation, and regulation of intermediates such as succinylaminoimidazole carboxamide ribotide (SAICAR), which functionally intersects with glycolysis and transcriptional control. In PDAC, dysregulation of ADSL-associated metabolism has been linked to aggressive tumor biology and altered therapeutic responses. Mechanistically, ADSL may modulate gemcitabine responsiveness through context-dependent effects on purine nucleotide homeostasis, replication-stress adaptation, redox regulation, and ferroptosis-associated signaling. Beyond its canonical biosynthetic function, ADSL-related metabolic flux may support adaptive survival through SAICAR-pyruvate kinase M2 (PKM2) signaling, glycolytic remodeling, and fumarate-associated pathways that influence redox homeostasis, epigenetic regulation, and stress-response signaling. These interconnected mechanisms position ADSL as a context-dependent metabolic vulnerability in chemoresistant PDAC. Here, we summarize current understanding of ADSL biology and discuss its prognostic, mechanistic, and therapeutic relevance in PDAC chemoresistance, with emphasis on gemcitabine resistance, replication stress buffering, and metabolic adaptation. Targeting ADSL-associated metabolic dependencies may provide a promising strategy to disrupt the metabolic circuitry underlying PDAC aggressiveness and drug resistance.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"29"},"PeriodicalIF":4.6,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial LINC01133 regulates pyroptosis and calcium homeostasis in cisplatin-resistant lung adenocarcinoma.","authors":"Feiyi Xu, Can Zhang, Sihan Wu, Yang Li, Yonggang Chen, Youwei Zhang","doi":"10.20517/cdr.2026.39","DOIUrl":"10.20517/cdr.2026.39","url":null,"abstract":"<p><p><b>Aim</b>: Cisplatin (DDP) represents the first-line chemotherapeutic agent for lung adenocarcinoma (LUAD), but acquired resistance severely limits its efficacy. This study investigated the role of the mitochondria-associated long non-coding RNA (mt-lncRNA) LINC01133 and its mechanisms in cisplatin resistance in LUAD. <b>Methods:</b> LINC01133 expression and subcellular localization were detected through high-throughput mitochondrial RNA sequencing, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and fluorescence <i>in situ</i> hybridization (FISH). By modulating LINC01133 expression, we evaluated its effect on cisplatin resistance and malignant phenotypes. Further, western blotting, enzyme-linked immunosorbent assays (ELISAs), and calcium fluorescent probes were used to analyze how LINC01133 affects the Caspase-1/GSDMD signaling pathway, mitochondrial calcium homeostasis, and mitochondrial function. Finally, <i>in vitro</i> rescue experiments and a xenograft mouse model were conducted to validate the function of LINC01133 and its key targets. <b>Results:</b> LINC01133 expression markedly increased in A549/DDP cells and was enriched in mitochondria. Clinical analysis revealed a difference in LINC01133 expression between LUAD and normal lung tissues, and higher LINC01133 expression was associated with poor patient survival. Functionally, LINC01133 overexpression enhanced cisplatin resistance and malignant phenotypes in A549 cells, whereas its knockdown reversed the resistance phenotype and inhibited malignant behaviors in A549/DDP cells. Mechanistically, cisplatin triggered the Caspase-1/GSDMD pathway to induce pyroptosis. LINC01133 inhibited activation of this pathway, alleviating GSDMD-NT-mediated mitochondrial calcium overload and thereby preserving mitochondrial structural integrity and function, ultimately enhancing cisplatin resistance. <b>Conclusion:</b> LINC01133, a mitochondria-enriched oncogenic lncRNA, promotes cisplatin resistance in LUAD by inhibiting the Caspase-1/GSDMD pathway and maintaining mitochondrial calcium homeostasis and function.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"28"},"PeriodicalIF":4.6,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TET2 downregulation limits oxidative stress-induced cytotoxicity of high dose ascorbate in dabrafenib-resistant melanoma cells.","authors":"Eleicy Nathaly Mendoza, Serena Castelli, Angela De Cristofaro, Enrico Desideri, Grazia Graziani, Pedro Miguel Lacal, Maria Rosa Ciriolo, Fabio Ciccarone","doi":"10.20517/cdr.2026.42","DOIUrl":"10.20517/cdr.2026.42","url":null,"abstract":"<p><p><b>Aim:</b> This study investigates the role of Ten-Eleven Translocation (TET) dioxygenases in melanoma-acquired resistance to BRAF inhibitors (BRAFi), focusing on their contributions to epigenetic remodeling and redox balance. <b>Methods:</b> Dabrafenib-resistant A375 and M14 melanoma cell lines were generated and analyzed for TET family expression. Transcriptomic data from independent RNA-seq datasets of BRAFi-resistant melanoma models were used for validation. Cells were treated with high-dose L-ascorbic acid (ASC), a cofactor enhancing TET activity, and assessed for 5-hydroxymethylcytosine (5hmC) levels, reactive oxygen species (ROS) production, and cytotoxicity. Antioxidant capacity and expression of GLUT1, a transporter for oxidized ASC, were evaluated. TET2 was silenced to determine its functional role in ASC-mediated effects. <b>Results:</b> BRAFi-resistant cells displayed reduced TET2 expression and altered levels of other TET family members, consistent with RNA-seq data. ASC treatment increased 5hmC levels and induced ROS-dependent cytotoxicity predominantly in parental cells, while resistant cells were less sensitive. Resistant cells exhibited enhanced antioxidant defenses and reduced GLUT1 expression. TET2 silencing diminished ASC-induced 5hmC accumulation, ROS production, and GLUT1 expression, indicating a central role for TET2 in mediating ASC cytotoxicity. <b>Conclusion:</b> These findings identify a TET2-dependent epigenetic-metabolic axis that regulates redox vulnerability in melanoma. The link between TET2 activity, GLUT1 expression, and ROS-mediated cytotoxicity highlights potential biomarkers and therapeutic targets to overcome resistance to BRAFi.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"27"},"PeriodicalIF":4.6,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic roles and clinical applications of tertiary lymphoid structures in colorectal cancer drug resistance.","authors":"Zhiliang Li, Wenqing Jia, Zichao Guo, Fang Zheng, Chenhao Huang, Tao Zhang, Zhuoqing Xu, Haoran Feng, Xi Cheng, Ren Zhao","doi":"10.20517/cdr.2026.35","DOIUrl":"10.20517/cdr.2026.35","url":null,"abstract":"<p><p>Therapeutic resistance represents a formidable bottleneck in colorectal cancer (CRC) management, severely limiting the clinical efficacy of both conventional regimens and novel immunotherapies. Emerging evidence underscores tertiary lymphoid structure (TLS) - ectopic lymphoid aggregates newly sculpted within the tumor microenvironment (TME) - as pivotal orchestrators of localized antitumor immunity and prime therapeutic targets to circumvent resistance. Distinct from secondary lymphoid organs, TLS facilitate <i>in situ</i> immune cell priming, clonal expansion, and functional differentiation, thereby sustaining a robust adaptive immune response. This review systematically dissects the cellular architecture, maturation dynamics, and spatial heterogeneity of TLS in primary and metastatic CRC, clarifying how these attributes dictate clinical outcomes and treatment responsiveness. Mechanistically, we delineate the molecular networks driving TLS neogenesis, encompassing chemokine cascades, tumor necrosis factor (TNF) superfamily signaling, and interactive crosstalk with the gut microbiota. Furthermore, we summarize cutting-edge preclinical strategies - including stimulator of interferon genes agonists, bio-nanovaccines, and hypofractionated radiotherapy combinations - engineered to trigger TLS neogenesis, promote germinal center (GC) maturation, and enrich stem-like effector tumor-infiltrating lymphocytes (TILs) to convert immunologically \"cold\" tumors into \"hot\" niches. By integrating mechanistic paradigms with clinical applications, this review provides a definitive framework for leveraging TLS targeting as a transformative modality to modulate drug resistance and optimize therapeutic trajectories in CRC; the graphical abstract is shown below.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"9 ","pages":"26"},"PeriodicalIF":4.6,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148714702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}