Drug Resistance Updates最新文献

{"title":"Three decades of ESKAPEE antimicrobial resistance: Emerging burdens in working-age individuals and high-income regions","authors":"Xiuling Song, Liang Wang, Bing Gu","doi":"10.1016/j.drup.2025.101325","DOIUrl":"10.1016/j.drup.2025.101325","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101325"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498786","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":"Metabolic basis of fatty acid oxidation and immunotherapy resistance with clinical perspectives","authors":"Junfeng Zhang, Jianyou Gu","doi":"10.1016/j.drup.2025.101317","DOIUrl":"10.1016/j.drup.2025.101317","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101317"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363516","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":"Loss of cyclin C drives resistance to anti-TIGIT therapy by upregulating CD155-mediated immune evasion","authors":"Shiyu Mao ,&nbsp;Yadong Guo ,&nbsp;Chengyuan Dong ,&nbsp;Dongdong Wang ,&nbsp;Xinbo Wang ,&nbsp;Linjun Weng ,&nbsp;Yanrong Yang ,&nbsp;Yaxu Li ,&nbsp;Tingting Niu ,&nbsp;Qi Wu ,&nbsp;Zening Zheng ,&nbsp;Zezhi Shan ,&nbsp;Xiao Tan ,&nbsp;Yaohui Gao ,&nbsp;Jiali Jin ,&nbsp;Ping Wang ,&nbsp;Xin Ge ,&nbsp;Bing Shen ,&nbsp;Xudong Yao ,&nbsp;Lan Fang","doi":"10.1016/j.drup.2025.101318","DOIUrl":"10.1016/j.drup.2025.101318","url":null,"abstract":"<div><h3>Aims</h3><div>CD155 is an immune checkpoint protein expressed in tumor cells that interacts with its ligand T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on natural killer (NK) cells and T cells, mediating inhibitory regulation on immune cells. Blockade of the CD155-TIGIT interaction has demonstrated clinical benefits in patients with advanced cancers. The transcriptional and post-translational mechanisms governing CD155 expression remain largely unknown.</div></div><div><h3>Methods</h3><div>To identify regulators of CD155, we conducted a genome-wide CRISPR-Cas9 screen in cancer cells. Surface CD155 protein levels were analyzed via flow cytometry. The role of candidate regulators was validated through loss- and gain-of-function experiments with flow cytometry, Western blot, quantitative PCR, and chromatin immunoprecipitation (ChIP) assays. Additionally, ubiquitination assay was performed to examine post-translational modifications. Functional studies, including NK and T cell cytotoxicity assays, were conducted to assess the immune modulatory effects of CD155 regulation. Clinical relevance was evaluated by analyzing Cyclin C (CCNC) and CD155 expression in datasets of cancer patients who underwent immune checkpoint blockade therapy.</div></div><div><h3>Results</h3><div>The CRISPR-Cas9 screen identified CCNC as a transcriptional suppressor of CD155. <em>CCNC</em> knockout led to increased surface CD155 expression in cancer cell lines. Mechanistically, CCNC inhibited CD155 transcription by suppressing the activity of the transcription factor FOSL2. Furthermore, CCNC was found to be ubiquitinated and degraded by the E3 ubiquitin ligase FBXO11, suggesting a post-translational regulatory mechanism. Functionally, loss of CCNC promoted CD155 upregulation, thereby enhancing tumor immune evasion from NK and T cell-mediated responses. Clinically, CCNC expression was negatively correlated with CD155 levels in cancer patients, particularly those receiving immune checkpoint blockade therapy.</div></div><div><h3>Conclusion</h3><div>This study identifies a previously unrecognized master regulator CCNC that functions as a suppressor of CD155-mediated cancer immune evasion. The findings of this study suggest that tumors with low CCNC expression may be resistant to monotherapy and highlight a combination immunotherapy (TIGIT/PD-1 co-blockade) as a promising anti-cancer therapeutic strategy to overcome immune evasion in CCNC-deficient tumors.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101318"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485479","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":"Microbiota in drug resistance","authors":"Ru Jia ,&nbsp;Chuan-xing Xiao ,&nbsp;Yong-hai Zhang ,&nbsp;Li-yang Hu ,&nbsp;Y. Jun-jun ,&nbsp;Rui Zuo ,&nbsp;Yu-fei Hu ,&nbsp;Yu-hao Xie ,&nbsp;Xue-lei Ma ,&nbsp;Qi Li ,&nbsp;Kai-jian Hou","doi":"10.1016/j.drup.2025.101311","DOIUrl":"10.1016/j.drup.2025.101311","url":null,"abstract":"<div><div>Drug resistance, particularly those of anticancer drugs and antibiotics, poses a significant challenge in the treatment of diseases, severely compromising therapeutic efficacy and patient survival rates. In recent years, an increasing number of studies have highlighted the dual role of microbiota in either promoting or mitigating drug resistance. The microbiome exists in symbiosis with the host, playing a crucial role in maintaining physiological functions and regulating immune responses. However, dysbiosis within the microbial community may induce or exacerbate drug resistance. While antibiotic-mediated depletion of gut microbiota has been proposed as a strategy to combat resistance, it may paradoxically lead to increased resistance or even worsen treatment outcomes. In this review, we focus on anticancer and antimicrobial agents as representative examples to elucidate the association of microbiome and drug resistance. We provide a detailed discussion on the mechanisms by which microbial dysbiosis contributes to development of drug resistance. Additionally, we systematically summarize the latest advancements in microbiota-targeted therapeutic strategies aimed at overcoming resistance, including fecal microbiota transplantation, probiotics and prebiotics, and bacterial engineering approaches. Finally, we discuss the potential clinical applications of microbiota-modulating strategies for overcoming drug resistance and examine the current challenges and future research directions in this field.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101311"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158877","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":"Y10 phosphorylation of LDHA promotes the release of extracellular vesicle-derived circSEPT9 to enhance the chemoresistance of triple negative breast cancer cells via modulation of miR-515–5p/KIAA1429 axis","authors":"Yueping Wang ,&nbsp;Ziyun Zhang ,&nbsp;Juan Gu ,&nbsp;Ming Zhou ,&nbsp;Jiankang Huang ,&nbsp;Daoping Zhou ,&nbsp;Xuedong Wang","doi":"10.1016/j.drup.2025.101324","DOIUrl":"10.1016/j.drup.2025.101324","url":null,"abstract":"<div><h3>Objective</h3><div>Extracellular vesicle (EV)-derived RNAs play crucial roles in cancer biology and therapeutic resistance. This study investigated how EV-derived circSEPT9 mediates doxorubicin (DOX) resistance in triple negative breast cancer (TNBC).</div></div><div><h3>Methods</h3><div>TNBC tissues and samples were analyzed alongside MDA-MB-231 and MDA-MB-231/ADR cells. The molecular interplay among circSEPT9, KIAA1429, and miR-515–5p was explored to elucidate the regulatory axis underlying drug resistance. EVs were purified to assess the clinical diagnostic potential of EV-circSEPT9. Functional assays employing lactate dehydrogenase A (LDHA) knockdown and rescue with Flag-tagged human LDHA WT or Y10F mutant constructs were conducted to examine the significance of LDHA Y10 phosphorylation in EV-circSEPT9 release and DOX resistance.</div></div><div><h3>Results</h3><div>circSEPT9 silencing impaired proliferation, invasion, and colony formation of DOX-resistant TNBC cells while increasing their sensitivity to DOX through suppression of KIAA1429-mediated m6A modification. EVs from resistant cells transferred circSEPT9 to sensitive cells, thereby enhancing their drug resistance and tumor growth capacity. LDHA Y10 phosphorylation was found to be indispensable for EV-circSEPT9 secretion and the subsequent intercellular transfer of DOX resistance.</div></div><div><h3>Conclusion</h3><div>Phosphorylated LDHA (Y10) promotes EV-circSEPT9 secretion, elevating intracellular circSEPT9 levels in recipient TNBC cells. By functioning as a competing endogenous RNA (ceRNA) that sponges miR-515–5p, circSEPT9 upregulates KIAA1429, augments m6A methylation, and drives the development of chemoresistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101324"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462288","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":"Polymeric micellar paclitaxel, cisplatin, and tislelizumab as first-line therapy for advanced unresectable esophageal squamous cell carcinoma: A phase II study with resistance profiling in poor responders","authors":"Caolu Liu ,&nbsp;Zipeng Wu ,&nbsp;Yingying Dai ,&nbsp;Shuyi Hu ,&nbsp;Lei Xia ,&nbsp;Xiaoyou Li ,&nbsp;Ruofan Yu ,&nbsp;Tianyi Liu ,&nbsp;Jingwen Li ,&nbsp;Fei Yan ,&nbsp;Lin Lu ,&nbsp;Yue Shi ,&nbsp;Yingying Jiang ,&nbsp;Jinghua Zhu ,&nbsp;Bo Shen ,&nbsp;Guoren Zhou ,&nbsp;Delin Liu ,&nbsp;Guochun Cao ,&nbsp;Xiaohua Wang ,&nbsp;Cheng Chen","doi":"10.1016/j.drup.2025.101300","DOIUrl":"10.1016/j.drup.2025.101300","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the efficacy and safety of polymeric micellar paclitaxel (Pm-Pac), cisplatin, and tislelizumab as first-line therapy for advanced/metastatic esophageal squamous cell carcinoma (ESCC), addressing limitations of conventional paclitaxel regimens related to steroid-induced immunosuppression.</div></div><div><h3>Methods</h3><div>This phase II clinical trial enrolled 27 treatment-naïve patients with stage IV ESCC. The regimen consisted of Pm-Pac (230 mg/m²), cisplatin (70 mg/m²), and tislelizumab (200 mg) administered on day 1 of 21-day cycles. After two induction cycles, non-progressive patients received two additional cycles, followed by 12-month tislelizumab maintenance. Primary endpoint: objective response rate (ORR); secondary endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Exploratory analyses included blood counts, tumor markers, lymphocyte subsets, survival analysis, Kruskal-Wallis tests, clustering, and LASSO regression.</div></div><div><h3>Results</h3><div>The regimen achieved an ORR of 62.96 % (95 % CI: 0.45–0.81) with complete response (CR) in 7.4 % and partial response (PR) in 55.6 % of patients. Median PFS was 10.2 months, with 1-year OS probability of 81.48 %. Treatment was well-tolerated without grade ≥ 3 treatment-related adverse events or deaths. Exploratory predictive analyses suggested potential correlations between outcomes and hyperkalemia, CD4 +CD25 + T cells, lung metastases, and distant lymph node metastases.</div></div><div><h3>Conclusions</h3><div>The Pm-Pac-based chemoimmunotherapy suggests encouraging efficacy and favorable safety in advanced ESCC, supporting its potential as a first-line steroid-free option. These findings highlight the role of nanotechnology in optimizing chemoimmunotherapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101300"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082402","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":"Disruption of NANOG-driven epithelial-mesenchymal transition (EMT) and self-renewal restores drug sensitivity in colorectal cancer","authors":"Kiarash Saleki ,&nbsp;Sameerah Shaheen ,&nbsp;Miao Xue ,&nbsp;Amirreza Mazloomi ,&nbsp;Sepideh Youssefi ,&nbsp;Hossein Kashfi ,&nbsp;Mehreen Ahmed ,&nbsp;Roya Babaei-Jadidi ,&nbsp;Bradley Spencer-Dene ,&nbsp;Dominique Bonnet ,&nbsp;Chris Denning ,&nbsp;Abdolrahman S. Nateri","doi":"10.1016/j.drup.2025.101321","DOIUrl":"10.1016/j.drup.2025.101321","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the regulatory role of NANOG in genes associated with stemness, symmetric division, and therapeutic resistance in colorectal cancer stem-like cells (CRC-SCs), with a focus on ERK/GSK-3β/β-catenin signalling and epithelial-mesenchymal transition (EMT), in order to evaluate the translational potential of targeting NANOG-associated signalling pathways.</div></div><div><h3>Methods</h3><div>Stemness, signalling activity, and cell division modes were analysed using 3D colonospheres enriched for CRC-SCs. Drug responses to the MEK inhibitor U0126 and the GSK-3β inhibitor TDZD-8 were assessed in CRC patient-derived organoids (PDOs), alongside molecular assays, immunohistochemistry with H-score quantification in xenograft models, and molecular dynamics simulations.</div></div><div><h3>Results</h3><div>NANOG overexpression enhanced the expression of stemness-associated genes, promoted symmetric cell division, and activated ERK/GSK-3β signalling, contributing to increased sphere formation. Inhibition of MEK and GSK-3β reduced EMT, cell proliferation, and symmetric division in CRC-SCs. NANOG-mediated dysregulation of ERK/GSK-3β altered β-catenin signalling and disrupted E-cadherin-dependent cell-cell adhesion. Molecular simulations and drug assays demonstrated that TDZD-8 and U0126 interfere with NANOG-DNA binding and β-catenin/E-cadherin interactions.</div></div><div><h3>Conclusions</h3><div>NANOG drives CRC-SC maintenance via ERK/GSK-3β/β-catenin signalling and EMT modulation. This study offers significant insights into the translational impact of targeting NANOG and its downstream pathways with small-molecule inhibitors U0126 and TDZD-8 and presents a promising strategy to reduce CRC-SCs stemness, functionality, and tumourigenicity.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101321"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441940","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":"Staphylococcus aureus manipulates osteocytes to cause persistent chronic osteomyelitis and antibiotic resistance via pyroptosis pathway suppression","authors":"Yuanqing Cai ,&nbsp;Hongxin Hu ,&nbsp;Yang Chen ,&nbsp;Jiayu Li ,&nbsp;Chaofan Zhang ,&nbsp;Xuhui Yuan ,&nbsp;Wenbo Li ,&nbsp;Changyu Huang ,&nbsp;Yiming Lin ,&nbsp;Zeyu Zhang ,&nbsp;Bin Yang ,&nbsp;Zida Huang ,&nbsp;Wenming Zhang ,&nbsp;Xinyu Fang","doi":"10.1016/j.drup.2025.101295","DOIUrl":"10.1016/j.drup.2025.101295","url":null,"abstract":"<div><h3>Aims</h3><div>In chronic osteomyelitis, the cortical bone serves as the primary site for long-term persistence of <em>Staphylococcus aureus</em> (<em>S. aureus</em>), the present study aimed to explore the mechanisms of immune evasion and antibiotic resistance remain incompletely understood.</div></div><div><h3>Methods</h3><div>Clinical methicillin-resistant <em>S. aureus</em> (MRSA) isolates, were collected and analyzed. Panton-Valentine leukocidin (PVL) expression levels were quantified via real-time PCR. The impact of PVL on pyroptosis was evaluated by infecting osteocytes and measuring caspase-1 activation and IL-1β release. Osteoclastogenesis and pathological bone formation were examined through TRAP staining and micro-CT. To assess therapeutic potential, pyroptosis was pharmacologically induced using disodium 4,4’-dimethoxy-5,6,5’,6’-dimethylene dioxybiphenyl-2,2’-disulfonate (DMB), followed by evaluation of antibiotic efficacy and bone remodeling in osteomyelitis model.</div></div><div><h3>Results</h3><div>We observed in clinical cases that the survival rate of MRSA small colony variants (SCVs) in cortical bone is higher than that of non-SCV strains, with SCVs demonstrating characteristic antibiotic resistance through reduced metabolic activity. The PCR results demonstrated that compared to wild-type, MRSA SCVs exhibited significantly reduced expression levels of PVL, this low-PVL-expression phenotype markedly suppresses the activation of the pyroptosis pathway following infection. Furthermore, we discovered that during the adaptation to the intra-cortical environment, the global regulatory factor Sae and the protease aureolysin mediate the active downregulation of PVL, which resulted in targeted inhibition of osteocyte pyroptosis. The suppression of osteocyte pyroptosis simultaneously diminishes the host immune response, MRSA colonization, and antibiotics resistance. Pharmacological induction of pyroptosis via DMB significantly enhanced antibiotic efficacy, as well as alleviated pathological bone formation in chronic osteomyelitis.</div></div><div><h3>Conclusions</h3><div>MRSA modulates its own virulence factors to create a favorable space and environment for long-term survival within the cortical bone, and therapeutic strategies targeting osteocyte pyroptosis may represent a potential strategy of eradicating MRSA from cortical bone.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101295"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021104","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":"Beyond the boundary: The emerging roles of ATP-binding cassette transporters in multidrug resistance (MDR) and therapeutic targeting in cancer","authors":"Dongmei Sun ,&nbsp;Letao Bo ,&nbsp;Chao Jiang ,&nbsp;Yanning Lan ,&nbsp;Bohan Zhang ,&nbsp;Chao Zhang ,&nbsp;Zhe-Sheng Chen ,&nbsp;Yuying Fan","doi":"10.1016/j.drup.2025.101310","DOIUrl":"10.1016/j.drup.2025.101310","url":null,"abstract":"<div><div>Multidrug resistance (MDR) remains a primary obstacle to successful cancer chemotherapy, with the overexpression of ATP-binding cassette (ABC) transporters being a principal cause. These transporters actively efflux a wide range of anticancer drugs, reducing their intracellular efficacy. Consequently, targeting ABC transporters represents a critical strategy for overcoming therapeutic resistance. This comprehensive review details the molecular architecture and functional mechanisms of all seven human ABC transporter subfamilies (ABCA-ABCG), elucidating their distinct roles in both cancer progression and the development of MDR. We trace the evolution of therapeutic interventions, from first, second, and third-generation small molecule inhibitors to the potential of natural products. Furthermore, this review explores advanced and emerging strategies designed to circumvent or neutralize ABC transporter activity. These include genetic approaches such as RNA interference and CRISPR-Cas9 gene editing, immunotherapy-based tactics like monoclonal antibodies and antibody-drug conjugates (ADCs), and the application of sophisticated nanoparticle delivery systems designed to bypass efflux mechanisms. By providing a holistic overview of the entire ABC transporter family and the broad array of strategies being developed to counteract their function, this article aims to equip researchers with a full-scope perspective on the field, identifying current challenges and illuminating future directions for combating MDR in cancer.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101310"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093862","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":"Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic ductal adenocarcinoma","authors":"Maryam Safari ,&nbsp;Luigi Scotto ,&nbsp;Agnes Basseville ,&nbsp;Thomas Litman ,&nbsp;Haoran Xue ,&nbsp;Lubov Petrukhin ,&nbsp;Ping Zhou ,&nbsp;Helen E. Remotti ,&nbsp;Amy Ku ,&nbsp;Diana V. Morales ,&nbsp;Christopher Damoci ,&nbsp;Mingzhao Zhu ,&nbsp;Ravikanth Maddipati ,&nbsp;Kenneth G. Hull ,&nbsp;Robert W. Robey ,&nbsp;Kenneth P. Olive ,&nbsp;Tito Fojo ,&nbsp;Daniel Romo ,&nbsp;Susan E. Bates","doi":"10.1016/j.drup.2025.101312","DOIUrl":"10.1016/j.drup.2025.101312","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Emerging evidence suggests that epigenetic therapies have the potential to target key mechanisms driving PDAC progression and therapy resistance. Previous efforts to target KRAS-driven metabolic vulnerabilities, including dependence on enhanced fatty acid synthesis, have highlighted the potential for histone deacetylase (HDAC) inhibitors to deplete acetyl-CoA and induce DNA damage through histone acetylation, while resistance emerges at least in part due to the reversible nature of HDAC inhibitor-induced acetylation. In this work, we discovered that the combination of class I histone deacetylase (HDAC) inhibitors, such as romidepsin, with a novel RNA helicase eIF4A inhibitor, des-methyl pateamine A (DMPatA), induces robust and persistent hyperacetylation, significantly exceeding the levels and duration observed with HDAC inhibitor monotherapy. This combination synergistically reduces the viability of PDAC cells, even at low, nontoxic doses for both drugs. This unexpected synergistic effect triggers a cascade of cellular responses, including hypertranscription, metabolic stress, and augmented DNA damage. <em>Sustained hyperacetylation</em> represents a novel mechanism exploiting PDAC-specific vulnerabilities, simultaneously amplifying DNA damage and depleting acetyl-CoA levels critical for their aberrant proliferation. <em>In vivo</em>, the combination effectively suppresses tumor growth, showing no toxicity to normal tissues but sustained hyperacetylation in tumor tissue. The combination does not appear to induce known resistance mechanisms such as drug efflux; elevated MYC expression, rather than inducing resistance, sensitizes PDAC cells to treatment. These studies support translation of this synergistic combination to the clinic.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101312"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314190","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}