Pub Date : 2025-06-07DOI: 10.1016/j.drup.2025.101270
Chen Wang , Yaoyao Zhong , Senlin Xu , Wen Cai , Junwei Zhao , Jianmei Mao , Huaizhou Jin , Ching Ouyang , Yunfei Shi , Wing C. Chan , Wendong Huang , Jiawei Zhang , Ying Gu
T-cell lymphoma (TCL) is an aggressive malignancy with poor therapeutic outcomes, where glucocorticoid (GC) resistance remains a major challenge. Here, we identify TRIM24 as a critical regulator of GC receptor (GR) activity and a potential therapeutic target in TCL. TRIM24 deficiency delays TCL progression in murine models, suppresses cell proliferation, and enhances GC sensitivity by restoring GR transcriptional activity, as evidenced by transcriptomic and chromatin profiling. Mechanistically, TRIM24 interacts with Fused In Sarcoma (FUS) and promotes its liquid-liquid phase separation (LLPS) with GR, leading to impaired GR activity and heightened GC resistance. Moreover, TRIM24 is overexpressed in peripheral T-cell lymphoma (PTCL) samples, correlating with suppressed GR signaling and poor therapeutic response. These findings uncover an unrecognized “double-check” mechanism in which TRIM24 regulates nuclear GR function through FUS-facilitated LLPS. Importantly, targeting TRIM24 may provide a novel therapeutic strategy not only for overcoming GC resistance in TCL but also for addressing broader GR-dependent diseases.
{"title":"TRIM24 promotes T-cell lymphoma development and glucocorticoid resistance via FUS-mediated phase separation of the glucocorticoid receptor","authors":"Chen Wang , Yaoyao Zhong , Senlin Xu , Wen Cai , Junwei Zhao , Jianmei Mao , Huaizhou Jin , Ching Ouyang , Yunfei Shi , Wing C. Chan , Wendong Huang , Jiawei Zhang , Ying Gu","doi":"10.1016/j.drup.2025.101270","DOIUrl":"10.1016/j.drup.2025.101270","url":null,"abstract":"<div><div>T-cell lymphoma (TCL) is an aggressive malignancy with poor therapeutic outcomes, where glucocorticoid (GC) resistance remains a major challenge. Here, we identify TRIM24 as a critical regulator of GC receptor (GR) activity and a potential therapeutic target in TCL. TRIM24 deficiency delays TCL progression in murine models, suppresses cell proliferation, and enhances GC sensitivity by restoring GR transcriptional activity, as evidenced by transcriptomic and chromatin profiling. Mechanistically, TRIM24 interacts with Fused In Sarcoma (FUS) and promotes its liquid-liquid phase separation (LLPS) with GR, leading to impaired GR activity and heightened GC resistance. Moreover, TRIM24 is overexpressed in peripheral T-cell lymphoma (PTCL) samples, correlating with suppressed GR signaling and poor therapeutic response. These findings uncover an unrecognized “double-check” mechanism in which TRIM24 regulates nuclear GR function through FUS-facilitated LLPS. Importantly, targeting TRIM24 may provide a novel therapeutic strategy not only for overcoming GC resistance in TCL but also for addressing broader GR-dependent diseases.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101270"},"PeriodicalIF":15.8,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271564","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}
Pub Date : 2025-06-02DOI: 10.1016/j.drup.2025.101264
Xue Yang , Mengke Xu , Zhiqin Deng, Bo Xu
Cancer therapeutic resistance remains a formidable challenge due to its diverse underlying mechanisms. S-palmitoylation (or called S-acylation), a reversible post-translational modification involving the attachment of long-chain fatty acids to cysteine residues, has emerged as a critical regulator of cancer progression and treatment response. This review offers a comprehensive analysis of recent advancements in understanding the role of S-palmitoylation in cancer therapeutic resistance. We examine the intricate relationship between S-palmitoylation and major oncogenic pathways, with particular focus on its distinct contributions to resistance mechanisms in molecularly-targeted therapy, immunotherapy, chemotherapy, radiotherapy, and endocrine therapy. Additionally, we highlight the progress in the proteomic identification and characterization of S-palmitoylated proteins, as well as the development of selective inhibitors targeting protein acyltransferases (PATs) and acyl-protein thioesterases (APTs). Furthermore, we discuss the further directions for developing S-palmitoylation-targeted strategies, providing insights into potential avenues for overcoming cancer treatment resistance.
{"title":"The shadow of cancer therapeutic resistance: Unveiling the role of S-palmitoylation","authors":"Xue Yang , Mengke Xu , Zhiqin Deng, Bo Xu","doi":"10.1016/j.drup.2025.101264","DOIUrl":"10.1016/j.drup.2025.101264","url":null,"abstract":"<div><div>Cancer therapeutic resistance remains a formidable challenge due to its diverse underlying mechanisms. <em>S</em>-palmitoylation (or called <em>S</em>-acylation), a reversible post-translational modification involving the attachment of long-chain fatty acids to cysteine residues, has emerged as a critical regulator of cancer progression and treatment response. This review offers a comprehensive analysis of recent advancements in understanding the role of <em>S</em>-palmitoylation in cancer therapeutic resistance. We examine the intricate relationship between <em>S</em>-palmitoylation and major oncogenic pathways, with particular focus on its distinct contributions to resistance mechanisms in molecularly-targeted therapy, immunotherapy, chemotherapy, radiotherapy, and endocrine therapy. Additionally, we highlight the progress in the proteomic identification and characterization of <em>S</em>-palmitoylated proteins, as well as the development of selective inhibitors targeting protein acyltransferases (PATs) and acyl-protein thioesterases (APTs). Furthermore, we discuss the further directions for developing <em>S</em>-palmitoylation-targeted strategies, providing insights into potential avenues for overcoming cancer treatment resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101264"},"PeriodicalIF":15.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144231574","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}
Pub Date : 2025-06-02DOI: 10.1016/j.drup.2025.101265
Xinyue Wang , Anquan Shang , Haowei Chen , Jing Li , Yuan Jiang , Lili Wang , Shuai Qiu , Fenyong Sun , Chaoyan Yue
Objective
Utilizing Global Burden of Disease Study (GBD 2021) data, this study aims to illustrate trends and spatiotemporal patterns of multidrug-resistant tuberculosis (MDR-TB) burden from 1990 to 2021, and explore their potential mechanisms.
Methods
This research extracted core indicators including incidence, mortality, prevalence, and disability-adjusted life years (DALYs), with their age-standardized rate (ASR). Joinpoint regression, age-period-cohort analysis, inequality analysis, and frontier analysis were applied to describe the temporal and spatial trends of the disease burden. Decomposition analysis and risk factor analysis were performed to explore factors associated with MDR-TB burden fluctuation. Bayesian Age-Period-Cohort (BAPC) model was used to project the disease burden till 2050.
Results
Global MDR-TB cases and ASRs of all indicators rose from 1990 to 2021, with heavier burden in older populations and lower socioeconomic regions. Cross-country inequality widened over time. Frontier analysis identified countries including India and Russia with considerable potential for improvement in disease control. Decomposition analysis uncovered epidemiological changes as the main driver of the growing burden globally. Risk factors of MDR-TB in different regions and age groups were heterogeneous. The numbers and ASRs of all indicators are predicted to increase by 2050.
Conclusions
This study revealed that the global disease burden of MDR-TB increased from 1990 to 2021 and is predicted to grow till 2050. Disparities among different social-demographic regions were remarkable and extended over time. Epidemiological changes contributed most to the escalated disease burden. Targeted public health strategies should be adopted for patients in specific regions and age groups.
{"title":"Global, regional, and national disease burden of multidrug-resistant tuberculosis without extensive drug resistance, 1990–2021: Findings from the Global Burden of Disease Study 2021","authors":"Xinyue Wang , Anquan Shang , Haowei Chen , Jing Li , Yuan Jiang , Lili Wang , Shuai Qiu , Fenyong Sun , Chaoyan Yue","doi":"10.1016/j.drup.2025.101265","DOIUrl":"10.1016/j.drup.2025.101265","url":null,"abstract":"<div><h3>Objective</h3><div>Utilizing Global Burden of Disease Study (GBD 2021) data, this study aims to illustrate trends and spatiotemporal patterns of multidrug-resistant tuberculosis (MDR-TB) burden from 1990 to 2021, and explore their potential mechanisms.</div></div><div><h3>Methods</h3><div>This research extracted core indicators including incidence, mortality, prevalence, and disability-adjusted life years (DALYs), with their age-standardized rate (ASR). Joinpoint regression, age-period-cohort analysis, inequality analysis, and frontier analysis were applied to describe the temporal and spatial trends of the disease burden. Decomposition analysis and risk factor analysis were performed to explore factors associated with MDR-TB burden fluctuation. Bayesian Age-Period-Cohort (BAPC) model was used to project the disease burden till 2050.</div></div><div><h3>Results</h3><div>Global MDR-TB cases and ASRs of all indicators rose from 1990 to 2021, with heavier burden in older populations and lower socioeconomic regions. Cross-country inequality widened over time. Frontier analysis identified countries including India and Russia with considerable potential for improvement in disease control. Decomposition analysis uncovered epidemiological changes as the main driver of the growing burden globally. Risk factors of MDR-TB in different regions and age groups were heterogeneous. The numbers and ASRs of all indicators are predicted to increase by 2050.</div></div><div><h3>Conclusions</h3><div>This study revealed that the global disease burden of MDR-TB increased from 1990 to 2021 and is predicted to grow till 2050. Disparities among different social-demographic regions were remarkable and extended over time. Epidemiological changes contributed most to the escalated disease burden. Targeted public health strategies should be adopted for patients in specific regions and age groups.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101265"},"PeriodicalIF":15.8,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144255051","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}
Pub Date : 2025-05-29DOI: 10.1016/j.drup.2025.101261
Chenghui Yang , Yiying Xu , Zhongmin Lin , Anqi Zhang , Lili Li , Zhiqiang Ye , Qiongying Zhang , Hanwen Hu , Guohong Ren , Pu Cheng , Zhen Wang , Ouchen Wang
Background
The TCbHP regimen, consisting of combining docetaxel (T), carboplatin (Cb), trastuzumab (H), and pertuzumab (P), is the preferred neoadjuvant treatment for locally advanced human epidermal growth factor 2 (HER2)-positive breast cancer. However, about 40 % of patients develop resistance to this treatment. Adding TKIs like pyrotinib to anti-HER2 antibodies may enhance efficacy and reduce resistance, but the mechanisms are not fully understood.
Methods
Imaging mass cytometry (IMC) analyzed tissues from 26 patients treated with NeoPICD (docetaxel, carboplatin, pyrotinib, inetetamab) and 21 patients treated with TCbHP. Cellular changes and spatial relationships were assessed pre- and post-treatment. A co-culture system of tumor cells, fibroblasts, and PBMCs were used to examined cytotoxic T-cell function. A predictive model for treatment outcomes was constructed based on these results.
Results
In TCbHP-sensitive patients, IDOhiHLA-DRhi epithelial cells expressing PD-L1 were enriched and interacted with Ki67+ T cells and M1 macrophages. In TCbHP-resistant patients, fibroblasts formed a barrier that hindered immune cell access, critical for resistance. NeoPICD disrupted this barrier, enhancing immune cell infiltration and alleviating resistance. Machine learning based on spatial cell architecture can predict treatment outcomes.
Conclusion
Spatial organization of cellular interactions in the tumor microenvironment (TME) provides insights into prognosis beyond pathological subtypes. The role of NeoPICD in disruption of fibroblast barriers and enhancement of immune cell function suggests therapeutic advantages in overcoming resistance to anti-HER2 therapies. This research offers new strategies for precision treatment of locally advanced HER2-positive breast cancer.
{"title":"Spatial discovery of pyrotinib overcoming HER2-positive breast cancer resistance by breaking fibroblast-induced immune barriers","authors":"Chenghui Yang , Yiying Xu , Zhongmin Lin , Anqi Zhang , Lili Li , Zhiqiang Ye , Qiongying Zhang , Hanwen Hu , Guohong Ren , Pu Cheng , Zhen Wang , Ouchen Wang","doi":"10.1016/j.drup.2025.101261","DOIUrl":"10.1016/j.drup.2025.101261","url":null,"abstract":"<div><h3>Background</h3><div>The TCbHP regimen, consisting of combining docetaxel (T), carboplatin (Cb), trastuzumab (H), and pertuzumab (P), is the preferred neoadjuvant treatment for locally advanced human epidermal growth factor 2 (HER2)-positive breast cancer. However, about 40 % of patients develop resistance to this treatment. Adding TKIs like pyrotinib to anti-HER2 antibodies may enhance efficacy and reduce resistance, but the mechanisms are not fully understood.</div></div><div><h3>Methods</h3><div>Imaging mass cytometry (IMC) analyzed tissues from 26 patients treated with NeoPICD (docetaxel, carboplatin, pyrotinib, inetetamab) and 21 patients treated with TCbHP. Cellular changes and spatial relationships were assessed pre- and post-treatment. A co-culture system of tumor cells, fibroblasts, and PBMCs were used to examined cytotoxic T-cell function. A predictive model for treatment outcomes was constructed based on these results.</div></div><div><h3>Results</h3><div>In TCbHP-sensitive patients, IDO<sup>hi</sup>HLA-DR<sup>hi</sup> epithelial cells expressing PD-L1 were enriched and interacted with Ki67<sup>+</sup> T cells and M1 macrophages. In TCbHP-resistant patients, fibroblasts formed a barrier that hindered immune cell access, critical for resistance. NeoPICD disrupted this barrier, enhancing immune cell infiltration and alleviating resistance. Machine learning based on spatial cell architecture can predict treatment outcomes.</div></div><div><h3>Conclusion</h3><div>Spatial organization of cellular interactions in the tumor microenvironment (TME) provides insights into prognosis beyond pathological subtypes. The role of NeoPICD in disruption of fibroblast barriers and enhancement of immune cell function suggests therapeutic advantages in overcoming resistance to anti-HER2 therapies. This research offers new strategies for precision treatment of locally advanced HER2-positive breast cancer.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101261"},"PeriodicalIF":15.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212810","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}
Pub Date : 2025-05-20DOI: 10.1016/j.drup.2025.101254
Heng Heng , Ruanyang Sun , Xuemei Yang , Lianwei Ye , Kaichao Chen , Jun Li , Edward Wai-Chi Chan , Rungsheng Li , Rong Zhang , Sheng Chen
The emergence and spread of carbapenem resistance (CR) and hypervirulence (hv) in Klebsiella pneumoniae represent a growing global health threat. Plasmids play an important role in the dissemination of these traits; however, the plasmidome of draft genomes of a large number of K. pneumoniae has not been analyzed so far. To recover K. pneumoniae plasmids, OMAP-KP was developed, achieving a recall rate of 85.27 % for plasmids exceeding 10,000 bp in length from draft genomes. From a global collection of 69,969 K. pneumoniae genomes, we identified 226,110 plasmids, providing the most comprehensive profiling of the K. pneumoniae plasmidome to date. The study recovered 12,790 KPC-encoding plasmids, 6214 NDM-encoding plasmids, and 6843 hv plasmids. Plasmid KPC PC_392 was found to be associated with ST11 K. pneumoniae in China, featuring the klcA within the genetic context around blaKPC. NDM plasmids exhibited a widespread distribution, and stabilization began before 2015. There was an increased prevalence of blaNDM-5 with the qnrS1 gene compared to blaNDM-1 after 2020. The frequent convergence of CR and hv plasmid pairs was observed in different STs: hv PC_499 with KPC PC_362 (ST11) and OXA PC_7078 (ST15), and hv PC_394 with OXA PC_7078 (ST2096) and OXA PC_804 (ST383), suggesting clone transmission of K. pneumoniae carrying CR-hv plasmid pairs. Alarmingly, PC_394 can encode both hv loci and CR genes, with an increasing prevalence detected from the public database from North America and Europe & Central Asia after 2019, which might result from the change of isolation or treatment strategy, or potentially from the ongoing spread of plasmids that have not been detected in other areas. This observed pattern coincides with the period of the COVID-19 pandemic needs further investigation. This study highlights the potential to integrate plasmid-level analysis into genome surveillance projects. The plasmidome reference and identification approach can track the emergence and convergence of CR and hv PCs in the evolution and transmission of K. pneumoniae, paving the way for more effective interventions to protect public health.
{"title":"Profiling the landscape of carbapenem resistance and hypervirulence in Klebsiella pneumoniae: A global epidemiological analysis of the plasmidome","authors":"Heng Heng , Ruanyang Sun , Xuemei Yang , Lianwei Ye , Kaichao Chen , Jun Li , Edward Wai-Chi Chan , Rungsheng Li , Rong Zhang , Sheng Chen","doi":"10.1016/j.drup.2025.101254","DOIUrl":"10.1016/j.drup.2025.101254","url":null,"abstract":"<div><div>The emergence and spread of carbapenem resistance (CR) and hypervirulence (hv) in <em>Klebsiella pneumoniae</em> represent a growing global health threat. Plasmids play an important role in the dissemination of these traits; however, the plasmidome of draft genomes of a large number of <em>K. pneumoniae</em> has not been analyzed so far. To recover <em>K. pneumoniae</em> plasmids, OMAP-KP was developed, achieving a recall rate of 85.27 % for plasmids exceeding 10,000 bp in length from draft genomes. From a global collection of 69,969 <em>K. pneumoniae</em> genomes, we identified 226,110 plasmids, providing the most comprehensive profiling of the <em>K. pneumoniae</em> plasmidome to date. The study recovered 12,790 KPC-encoding plasmids, 6214 NDM-encoding plasmids, and 6843 hv plasmids. Plasmid KPC PC_392 was found to be associated with ST11 <em>K. pneumoniae</em> in China, featuring the <em>klcA</em> within the genetic context around <em>bla</em><sub>KPC</sub>. NDM plasmids exhibited a widespread distribution, and stabilization began before 2015. There was an increased prevalence of <em>bla</em><sub>NDM-5</sub> with the <em>qnrS1</em> gene compared to <em>bla</em><sub>NDM-1</sub> after 2020. The frequent convergence of CR and hv plasmid pairs was observed in different STs: hv PC_499 with KPC PC_362 (ST11) and OXA PC_7078 (ST15), and hv PC_394 with OXA PC_7078 (ST2096) and OXA PC_804 (ST383), suggesting clone transmission of <em>K. pneumoniae</em> carrying CR-hv plasmid pairs. Alarmingly, PC_394 can encode both hv loci and CR genes, with an increasing prevalence detected from the public database from North America and Europe & Central Asia after 2019, which might result from the change of isolation or treatment strategy, or potentially from the ongoing spread of plasmids that have not been detected in other areas. This observed pattern coincides with the period of the COVID-19 pandemic needs further investigation. This study highlights the potential to integrate plasmid-level analysis into genome surveillance projects. The plasmidome reference and identification approach can track the emergence and convergence of CR and hv PCs in the evolution and transmission of <em>K. pneumoniae</em>, paving the way for more effective interventions to protect public health.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101254"},"PeriodicalIF":15.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123235","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}
Pub Date : 2025-05-13DOI: 10.1016/j.drup.2025.101249
Jia-Jia Cui , Cheng-Xian Guo , Jun Li , Ao-Xiang Guo , Zhao Zhang , Si-Yu Li , Lei-Yun Wang , Xiang-Bin Jia , Hui Guo , Kun Xia , Zheng-Mao Hu , Qian-Ying Ouyang , Yang Wang , Yu-Ting Xie , Zhao-Qian Liu , Jian-Ting Zhang , Wei Wu , Yong-Heng Chen , Ji-Ye Yin
Aims
Genotoxic drug resistance is one of the major obstacles for cancer treatment. Our previous study demonstrates that cold shock domain containing E1 (CSDE1) is associated with drug resistance. In this study, we aim to demonstrate that CSDE1 regulates cellular response to genotoxic drugs and to investigate its mechanism of action in drug resistance.
Methods
Tissues and blood samples from cancer patients were used to evaluate the relationship between CSDE1 and genotoxic drug response. Comet and immunofluorescence assays were conducted to investigate the role of CSDE1 in DNA damage repair. Systematic knockout mouse models were used to study the underlying mechanism involved. Biotin pull-down, EMSA and co-IP assays were used to probe the triplex structure of CSDE1-protein (eIF3a)-RNA (RPA2).
Results
CSDE1 elevation correlates with poor response in patient and increased resistance in cell lines to genotoxic drugs. CSDE1 upregulated the nucleotide excision repair (NER) and homologous recombination (HR) pathways. In X-ray irradiation or bleomycin-induced DNA damage mouse model, systemic CSDE1 knockout resulted in increased DNA damage. In both a CSDE1 knockout mouse model and cancer cell lines, CSDE1 inhibited the cGAS-STING pathway through RPA2. Mechanistic studies indicated that CSDE1 serves as a hub for the binding of the CSDE1-protein (eIF3a)-RNA (RPA2) ternary complex.
Conclusions
This study reveals the new role of CSDE1 in enhancing resistance to genotoxic drugs, and the detailed zipper-like cross ternary structural of CSDE1. It provides a new strategy for enhancing genotoxic drugs sensitivity.
{"title":"CSDE1 enhances genotoxic drug resistance in cancer by modulating RPA2 through CSDE1-eIF3a regulatory complex","authors":"Jia-Jia Cui , Cheng-Xian Guo , Jun Li , Ao-Xiang Guo , Zhao Zhang , Si-Yu Li , Lei-Yun Wang , Xiang-Bin Jia , Hui Guo , Kun Xia , Zheng-Mao Hu , Qian-Ying Ouyang , Yang Wang , Yu-Ting Xie , Zhao-Qian Liu , Jian-Ting Zhang , Wei Wu , Yong-Heng Chen , Ji-Ye Yin","doi":"10.1016/j.drup.2025.101249","DOIUrl":"10.1016/j.drup.2025.101249","url":null,"abstract":"<div><h3>Aims</h3><div>Genotoxic drug resistance is one of the major obstacles for cancer treatment. Our previous study demonstrates that cold shock domain containing E1 (CSDE1) is associated with drug resistance. In this study, we aim to demonstrate that CSDE1 regulates cellular response to genotoxic drugs and to investigate its mechanism of action in drug resistance.</div></div><div><h3>Methods</h3><div>Tissues and blood samples from cancer patients were used to evaluate the relationship between CSDE1 and genotoxic drug response. Comet and immunofluorescence assays were conducted to investigate the role of CSDE1 in DNA damage repair. Systematic knockout mouse models were used to study the underlying mechanism involved. Biotin pull-down, EMSA and co-IP assays were used to probe the triplex structure of CSDE1-protein (eIF3a)-RNA (RPA2).</div></div><div><h3>Results</h3><div>CSDE1 elevation correlates with poor response in patient and increased resistance in cell lines to genotoxic drugs. CSDE1 upregulated the nucleotide excision repair (NER) and homologous recombination (HR) pathways. In X-ray irradiation or bleomycin-induced DNA damage mouse model, systemic CSDE1 knockout resulted in increased DNA damage. In both a CSDE1 knockout mouse model and cancer cell lines, CSDE1 inhibited the cGAS-STING pathway through RPA2. Mechanistic studies indicated that CSDE1 serves as a hub for the binding of the CSDE1-protein (eIF3a)-RNA (RPA2) ternary complex.</div></div><div><h3>Conclusions</h3><div>This study reveals the new role of CSDE1 in enhancing resistance to genotoxic drugs, and the detailed zipper-like cross ternary structural of CSDE1. It provides a new strategy for enhancing genotoxic drugs sensitivity.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101249"},"PeriodicalIF":15.8,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089599","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}
Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K signalling axis and, particularly, in the PIK3CA gene. The promising rationale of using PI3K inhibitors for the treatment of HNSCC has, however, clashed with the spontaneous development of resistance over time.
Methods
To identify valuable targets for overcoming acquired resistance to PI3Kα inhibitors in HNSCC, we performed microRNA profiling on a cohort of HNSCC PDXs that were treated with alpelisib, including both responsive and resistant tumors. Using CRISPR/Cas9, siRNA, and PTEN-/- isogenic and alpelisib-resistant cell models, we examined the role of PTEN in resistance acquisition. Phospho-proteomic analysis identified PTEN-dependent phosphorylation events, while PI3Kα inhibitor-resistant organoids were used to assess PLK1 inhibitor efficacy.
Results
We identified microRNAs altered in resistant PDXs, including members of the miR-17–92 cluster. Mechanistically, we observed that the hyperactive c-Myc was recruited to MIR17HG regulatory regions in alpelisib-resistant cells, sustaining miR-17–5p, miR-19b-3p, and miR-20a-5p expression, which downregulated PTEN. PTEN knockout or depletion conferred alpelisib resistance in HNSCC cells. We identified PTEN-dependent phosphorylation events, such as p-PLK1-T210, involved in resistance. Interestingly, pharmacological inhibition of PLK1 strongly reduced the viability of PI3Kα-resistant organoids derived from HNSCC PDXs and cell line models.
Conclusion
Overall, this study unveils a novel, microRNA-driven, non-genetic mechanism contributing to acquired resistance to PI3Kα inhibitors in HNSCC. Indeed, linking hyperactive c-Myc to sustain miR-17–92 expression and consequent PTEN downregulation, we also propose that targeting PTEN-dependent downstream effectors, such as PLK1, may offer a powerful therapeutic strategy for resistant HNSCC.
{"title":"MicroRNA-mediated PTEN downregulation as a novel non-genetic mechanism of acquired resistance to PI3Kα inhibitors of head & neck squamous cell carcinoma","authors":"Claudio Pulito , Sebastiano Vaccarella , Alina Catalina Palcau , Federica Ganci , Renata Brandi , Carlotta Frascolla , Andrea Sacconi , Valeria Canu , Anna Benedetti , Valentina De Pascale , Sara Donzelli , Anne-Sophie Fisch , Valentina Manciocco , Renato Covello , Fulvia Pimpinelli , Aldo Morrone , Francesco Fazi , Raul Pellini , Paola Muti , Jalna Meens , Giovanni Blandino","doi":"10.1016/j.drup.2025.101251","DOIUrl":"10.1016/j.drup.2025.101251","url":null,"abstract":"<div><h3>Aims</h3><div>Head and neck squamous cell carcinomas (HNSCCs) frequently harbor alterations in the PI3K signalling axis and, particularly, in the PIK3CA gene. The promising rationale of using PI3K inhibitors for the treatment of HNSCC has, however, clashed with the spontaneous development of resistance over time.</div></div><div><h3>Methods</h3><div>To identify valuable targets for overcoming acquired resistance to PI3Kα inhibitors in HNSCC, we performed microRNA profiling on a cohort of HNSCC PDXs that were treated with alpelisib, including both responsive and resistant tumors. Using CRISPR/Cas9, siRNA, and PTEN-/- isogenic and alpelisib-resistant cell models, we examined the role of PTEN in resistance acquisition. Phospho-proteomic analysis identified PTEN-dependent phosphorylation events, while PI3Kα inhibitor-resistant organoids were used to assess PLK1 inhibitor efficacy.</div></div><div><h3>Results</h3><div>We identified microRNAs altered in resistant PDXs, including members of the miR-17–92 cluster. Mechanistically, we observed that the hyperactive c-Myc was recruited to MIR17HG regulatory regions in alpelisib-resistant cells, sustaining miR-17–5p, miR-19b-3p, and miR-20a-5p expression, which downregulated PTEN. PTEN knockout or depletion conferred alpelisib resistance in HNSCC cells. We identified PTEN-dependent phosphorylation events, such as p-PLK1-T210, involved in resistance. Interestingly, pharmacological inhibition of PLK1 strongly reduced the viability of PI3Kα-resistant organoids derived from HNSCC PDXs and cell line models.</div></div><div><h3>Conclusion</h3><div>Overall, this study unveils a novel, microRNA-driven, non-genetic mechanism contributing to acquired resistance to PI3Kα inhibitors in HNSCC. Indeed, linking hyperactive c-Myc to sustain miR-17–92 expression and consequent PTEN downregulation, we also propose that targeting PTEN-dependent downstream effectors, such as PLK1, may offer a powerful therapeutic strategy for resistant HNSCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101251"},"PeriodicalIF":15.8,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071120","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}
Pub Date : 2025-05-11DOI: 10.1016/j.drup.2025.101252
Bowen Ding , Xiaomeng Liu , Zhe Li , Xinru Xie , Jiaqi Li , Jiaqian Wang , Shouyi Li , Pengyu Wang , Yongjie Xie , Xiaoqing Ma , Hongwei Wang , Chengzhi Xie , Xin Qiao , Yumin Wang , Jingyuan Xu , Yukuan Feng , Jihui Hao
Platinum(II) (Pt(II)) drugs, such as cisplatin and oxaliplatin, played critical roles in cancer therapy; however, their efficacy is often limited by significant toxicity and the development of drug resistance. Recently, multi-target platinum(IV) (Pt(IV)) complexes, particularly those optimized with axial ligands, have emerged as promising alternatives enhancing tumor selectivity and drug stability. In this study, we synthesized a series of novel platinum(IV) prodrugs, gramine-platinum(IV), by incorporating gramine—a natural indole alkaloid that antagonizes TGF-β receptors I and II to inhibit the TGF-β signaling pathway—as an axial ligand. Among them, compound 8 (referred to as GP) was screened out to have the best antitumor activity. GP not only enhances the therapeutic efficacy of platinum(II) drugs but also targets TGF-β signaling. Our findings demonstrate that GP rapidly enters cells and preferentially accumulates in critical subcellular compartments, such as the nucleus and mitochondria, significantly amplifying its therapeutic impact. Notably, GP exhibits great tumor accumulation compared to cisplatin and oxaliplatin, with minimal uptake in normal tissues, highlighting its superior tumor specificity with reduced systemic toxicity. This unique characteristic enables GP to enhance therapeutic efficiency through multiple modalities, including strengthening DNA damage, reducing mitochondrial membrane potential, promoting apoptosis, and arresting cell cycle in the S phase. Moreover, GP activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling (cGAS-STING) pathway, enhancing antigen presentation and fostering robust anti-tumor immune responses. In mouse models of pancreatic and breast cancer, GP significantly inhibits tumor growth and triggers strong innate immune activation. By combining GP with anti-PD-1 therapy, immunotherapy-resistant tumors are rendered responsive, leading to a pronounced suppression of tumor growth. Overall, GP not only amplifies the DNA-damaging effects of platinum(II) drugs but also elicits durable immune responses, establishing itself as a promising chemo-immune-combined strategy for treating pancreatic and breast cancers.
{"title":"A novel platinum(IV) prodrug, gramine-Pt(IV) enhances chemoimmunotherapy by activating cGAS-STING and modulating TGF-β-MHC-I axis","authors":"Bowen Ding , Xiaomeng Liu , Zhe Li , Xinru Xie , Jiaqi Li , Jiaqian Wang , Shouyi Li , Pengyu Wang , Yongjie Xie , Xiaoqing Ma , Hongwei Wang , Chengzhi Xie , Xin Qiao , Yumin Wang , Jingyuan Xu , Yukuan Feng , Jihui Hao","doi":"10.1016/j.drup.2025.101252","DOIUrl":"10.1016/j.drup.2025.101252","url":null,"abstract":"<div><div>Platinum(II) (Pt(II)) drugs, such as cisplatin and oxaliplatin, played critical roles in cancer therapy; however, their efficacy is often limited by significant toxicity and the development of drug resistance. Recently, multi-target platinum(IV) (Pt(IV)) complexes, particularly those optimized with axial ligands, have emerged as promising alternatives enhancing tumor selectivity and drug stability. In this study, we synthesized a series of novel platinum(IV) prodrugs, gramine-platinum(IV), by incorporating gramine—a natural indole alkaloid that antagonizes TGF-β receptors I and II to inhibit the TGF-β signaling pathway—as an axial ligand. Among them, compound <strong>8</strong> (referred to as GP) was screened out to have the best antitumor activity. GP not only enhances the therapeutic efficacy of platinum(II) drugs but also targets TGF-β signaling. Our findings demonstrate that GP rapidly enters cells and preferentially accumulates in critical subcellular compartments, such as the nucleus and mitochondria, significantly amplifying its therapeutic impact. Notably, GP exhibits great tumor accumulation compared to cisplatin and oxaliplatin, with minimal uptake in normal tissues, highlighting its superior tumor specificity with reduced systemic toxicity. This unique characteristic enables GP to enhance therapeutic efficiency through multiple modalities, including strengthening DNA damage, reducing mitochondrial membrane potential, promoting apoptosis, and arresting cell cycle in the S phase. Moreover, GP activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling (cGAS-STING) pathway, enhancing antigen presentation and fostering robust anti-tumor immune responses. In mouse models of pancreatic and breast cancer, GP significantly inhibits tumor growth and triggers strong innate immune activation. By combining GP with anti-PD-1 therapy, immunotherapy-resistant tumors are rendered responsive, leading to a pronounced suppression of tumor growth. Overall, GP not only amplifies the DNA-damaging effects of platinum(II) drugs but also elicits durable immune responses, establishing itself as a promising chemo-immune-combined strategy for treating pancreatic and breast cancers.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101252"},"PeriodicalIF":15.8,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067198","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}
Pub Date : 2025-05-10DOI: 10.1016/j.drup.2025.101250
Jiashuai He , Yiran Zhang , Simin Luo , Zhan Zhao , Tianmu Mo , Hanyang Guan , Haoquan Li , Zili Bian , Xiangwei Zhang , Shenghui Qiu , Shijin Liu , Wang Tang , Bo Shi , Minfeng Chen , Dongmei Zhang , Yunlong Pan , Jinghua Pan
Colorectal cancer (CRC) with hepatic metastasis is associated with poor prognosis. Stereotactic body radiotherapy (SBRT) can provide local control for unresectable hepatic metastases of patients with CRC. However, the mechanisms of responsiveness to SBRT in metastatic CRC (mCRC) remain unclear. We aimed to identify a strategy to enhance the efficacy of SBRT in patients with CRC liver metastases and its mechanisms. Transcriptomic sequencing of CRC cells exposed to SBRT revealed that SBRT inhibited SLC7A11 expression. Downregulation of SLC7A11 enhanced the sensitivity of CRC cells to SBRT via ferroptosis. SBRT diminished the ability of tumor cells to sustain oxidative stress by impeding the phosphorylation of JNK and c-Jun and the transcription of NRF2. Furthermore, sorafenib, which targets SLC7A11, exerted inhibitory effects on tumor growth when used in combination with SBRT. A phase II clinical trial confirmed that sorafenib combined with SBRT overcame the resistance of liver mCRC with high SLC7A11 expression by inducing ferroptosis. The combination of SBRT and sorafenib demonstrated favorable clinical effects and safety, making it a good option for patients with CRC liver metastasis.
Statement of Significance
A novel strategy using the combination of SBRT and sorafenib for the treatment of patients with CRC hepatic metastasis was investigated. This strategy overcomes the radiation therapy resistance of mCRC by inhibiting SLC7A11 expression and promoting ferroptosis.
{"title":"Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis","authors":"Jiashuai He , Yiran Zhang , Simin Luo , Zhan Zhao , Tianmu Mo , Hanyang Guan , Haoquan Li , Zili Bian , Xiangwei Zhang , Shenghui Qiu , Shijin Liu , Wang Tang , Bo Shi , Minfeng Chen , Dongmei Zhang , Yunlong Pan , Jinghua Pan","doi":"10.1016/j.drup.2025.101250","DOIUrl":"10.1016/j.drup.2025.101250","url":null,"abstract":"<div><div>Colorectal cancer (CRC) with hepatic metastasis is associated with poor prognosis. Stereotactic body radiotherapy (SBRT) can provide local control for unresectable hepatic metastases of patients with CRC. However, the mechanisms of responsiveness to SBRT in metastatic CRC (mCRC) remain unclear. We aimed to identify a strategy to enhance the efficacy of SBRT in patients with CRC liver metastases and its mechanisms. Transcriptomic sequencing of CRC cells exposed to SBRT revealed that SBRT inhibited SLC7A11 expression. Downregulation of SLC7A11 enhanced the sensitivity of CRC cells to SBRT via ferroptosis. SBRT diminished the ability of tumor cells to sustain oxidative stress by impeding the phosphorylation of JNK and c-Jun and the transcription of NRF2. Furthermore, sorafenib, which targets SLC7A11, exerted inhibitory effects on tumor growth when used in combination with SBRT. A phase II clinical trial confirmed that sorafenib combined with SBRT overcame the resistance of liver mCRC with high SLC7A11 expression by inducing ferroptosis. The combination of SBRT and sorafenib demonstrated favorable clinical effects and safety, making it a good option for patients with CRC liver metastasis.</div></div><div><h3>Statement of Significance</h3><div>A novel strategy using the combination of SBRT and sorafenib for the treatment of patients with CRC hepatic metastasis was investigated. This strategy overcomes the radiation therapy resistance of mCRC by inhibiting SLC7A11 expression and promoting ferroptosis.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101250"},"PeriodicalIF":15.8,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067205","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}
Pub Date : 2025-04-30DOI: 10.1016/j.drup.2025.101244
Jintao He , Qiucheng Shi , Zhifu Chen , Wang Zhang , Peng Lan , Qingye Xu , Huangdu Hu , Qiong Chen , Jianzhong Fan , Yan Jiang , Belinda Loh , Sebastian Leptihn , Quanming Zou , Jinyong Zhang , Yunsong Yu , Xiaoting Hua
{"title":"Corrigendum to “Opposite evolution of pathogenicity driven by in vivo wzc and wcaJ mutations in ST11-KL64 carbapenem-resistant Klebsiella pneumoniae” [Drug Resist. Updat. 66 (2023) 100891]","authors":"Jintao He , Qiucheng Shi , Zhifu Chen , Wang Zhang , Peng Lan , Qingye Xu , Huangdu Hu , Qiong Chen , Jianzhong Fan , Yan Jiang , Belinda Loh , Sebastian Leptihn , Quanming Zou , Jinyong Zhang , Yunsong Yu , Xiaoting Hua","doi":"10.1016/j.drup.2025.101244","DOIUrl":"10.1016/j.drup.2025.101244","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101244"},"PeriodicalIF":15.8,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891423","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}
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