Drug Resistance Updates最新文献

{"title":"Profiling the landscape of carbapenem resistance and hypervirulence in Klebsiella pneumoniae: A global epidemiological analysis of the plasmidome","authors":"Heng Heng ,&nbsp;Ruanyang Sun ,&nbsp;Xuemei Yang ,&nbsp;Lianwei Ye ,&nbsp;Kaichao Chen ,&nbsp;Jun Li ,&nbsp;Edward Wai-Chi Chan ,&nbsp;Rungsheng Li ,&nbsp;Rong Zhang ,&nbsp;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>_KPC. NDM plasmids exhibited a widespread distribution, and stabilization began before 2015. There was an increased prevalence of <em>bla</em>_NDM-5 with the <em>qnrS1</em> gene compared to <em>bla</em>_NDM-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 <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 &amp; 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}

{"title":"CSDE1 enhances genotoxic drug resistance in cancer by modulating RPA2 through CSDE1-eIF3a regulatory complex","authors":"Jia-Jia Cui ,&nbsp;Cheng-Xian Guo ,&nbsp;Jun Li ,&nbsp;Ao-Xiang Guo ,&nbsp;Zhao Zhang ,&nbsp;Si-Yu Li ,&nbsp;Lei-Yun Wang ,&nbsp;Xiang-Bin Jia ,&nbsp;Hui Guo ,&nbsp;Kun Xia ,&nbsp;Zheng-Mao Hu ,&nbsp;Qian-Ying Ouyang ,&nbsp;Yang Wang ,&nbsp;Yu-Ting Xie ,&nbsp;Zhao-Qian Liu ,&nbsp;Jian-Ting Zhang ,&nbsp;Wei Wu ,&nbsp;Yong-Heng Chen ,&nbsp;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}

{"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 ,&nbsp;Sebastiano Vaccarella ,&nbsp;Alina Catalina Palcau ,&nbsp;Federica Ganci ,&nbsp;Renata Brandi ,&nbsp;Carlotta Frascolla ,&nbsp;Andrea Sacconi ,&nbsp;Valeria Canu ,&nbsp;Anna Benedetti ,&nbsp;Valentina De Pascale ,&nbsp;Sara Donzelli ,&nbsp;Anne-Sophie Fisch ,&nbsp;Valentina Manciocco ,&nbsp;Renato Covello ,&nbsp;Fulvia Pimpinelli ,&nbsp;Aldo Morrone ,&nbsp;Francesco Fazi ,&nbsp;Raul Pellini ,&nbsp;Paola Muti ,&nbsp;Jalna Meens ,&nbsp;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}

{"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 ,&nbsp;Xiaomeng Liu ,&nbsp;Zhe Li ,&nbsp;Xinru Xie ,&nbsp;Jiaqi Li ,&nbsp;Jiaqian Wang ,&nbsp;Shouyi Li ,&nbsp;Pengyu Wang ,&nbsp;Yongjie Xie ,&nbsp;Xiaoqing Ma ,&nbsp;Hongwei Wang ,&nbsp;Chengzhi Xie ,&nbsp;Xin Qiao ,&nbsp;Yumin Wang ,&nbsp;Jingyuan Xu ,&nbsp;Yukuan Feng ,&nbsp;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}

{"title":"Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis","authors":"Jiashuai He ,&nbsp;Yiran Zhang ,&nbsp;Simin Luo ,&nbsp;Zhan Zhao ,&nbsp;Tianmu Mo ,&nbsp;Hanyang Guan ,&nbsp;Haoquan Li ,&nbsp;Zili Bian ,&nbsp;Xiangwei Zhang ,&nbsp;Shenghui Qiu ,&nbsp;Shijin Liu ,&nbsp;Wang Tang ,&nbsp;Bo Shi ,&nbsp;Minfeng Chen ,&nbsp;Dongmei Zhang ,&nbsp;Yunlong Pan ,&nbsp;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}

{"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 ,&nbsp;Qiucheng Shi ,&nbsp;Zhifu Chen ,&nbsp;Wang Zhang ,&nbsp;Peng Lan ,&nbsp;Qingye Xu ,&nbsp;Huangdu Hu ,&nbsp;Qiong Chen ,&nbsp;Jianzhong Fan ,&nbsp;Yan Jiang ,&nbsp;Belinda Loh ,&nbsp;Sebastian Leptihn ,&nbsp;Quanming Zou ,&nbsp;Jinyong Zhang ,&nbsp;Yunsong Yu ,&nbsp;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}

{"title":"Long non-coding RNA LRTOR drives osimertinib resistance in non-small cell lung cancer by boosting YAP positive feedback loop","authors":"Zhimin Miao, Zhou Sha, Jianzhong He, Yongkai Liang, Lihua Tan, Yuxin Zhao, Xiaobing Cui, Jinmiao Zhong, Ruting Zhong, Huijun Liang, Wendi Yue, Boyang Qiu, Yunzhen Gao, Lan Zhang, Zixin Teng, Zeen He, Li Chen, Rufei Xiao, Xiaofeng Pei, Chengwei He","doi":"10.1016/j.drup.2025.101245","DOIUrl":"https://doi.org/10.1016/j.drup.2025.101245","url":null,"abstract":"The therapeutic efficacy of osimertinib (OSI) in EGFR-mutant lung cancer is ultimately limited by the onset of acquired resistance, of which the mechanisms remain poorly understood. Here, we identify a novel long non-coding RNA, LRTOR, as a key driver of OSI resistance in non-small cell lung cancer (NSCLC). Clinical data indicate that elevated LRTOR expression correlates with poor prognosis in OSI-resistant patients. Functionally, LRTOR promotes tumor growth and confers OSI resistance both <ce:italic>in vitro</ce:italic> and <ce:italic>in vivo</ce:italic>. Mechanistically, LRTOR shields YAP from LATS-mediated phosphorylation at Ser127 and Ser381, preventing its proteasomal degradation. Furthermore, LRTOR facilitates the interaction between YAP and KCMF1, promoting K63-linked ubiquitination, nuclear translocation of YAP, and formation of the YAP/TEAD1 transcriptional complex, which in turn triggers the transcription of LRTOR, establishing a positive feedback loop that amplifies oncogenic signaling of YAP and consequently induces OSI resistance. LRTOR depletion by siRNA restores OSI sensitivity in resistant tumors, as demonstrated in patient-derived organoid xenograft models. Our findings unveil LRTOR as a central regulator of OSI resistance in NSCLC and propose it as a promising therapeutic and prognostic target for overcoming acquired OSI resistance in EGFR-mutant lung cancer.","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"1 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901717","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":"Lactylation in cancer progression and drug resistance","authors":"Yuxiu Sun ,&nbsp;He Wang ,&nbsp;Zhe Cui ,&nbsp;Tingting Yu ,&nbsp;Yuanming Song ,&nbsp;Haolai Gao ,&nbsp;Ruihong Tang ,&nbsp;Xinlei Wang ,&nbsp;Binru Li ,&nbsp;Wenxin Li ,&nbsp;Zhe Wang","doi":"10.1016/j.drup.2025.101248","DOIUrl":"10.1016/j.drup.2025.101248","url":null,"abstract":"<div><div>Lactate plays a crucial role as an energy substrate, metabolite, and signaling molecule in cancer. Lactate has long been considered a byproduct of glycolysis. Still, the lactate shuttle hypothesis has changed the lactate paradigm, revealing the implications of lactate in cellular metabolism and cellular communications that can transcend the compartment barrier and occur within and between different cells, tissues, and organs. Due to the Warburg effect, the tumor produces a large amount of lactate, thus creating a low-nutrition, hypoxic, and low-pH tumor microenvironment (TME). Consequently, immunosuppressive networks are built to acquire immune evasion potential and regulate tumor growth. Lactylation is a newly discovered post-translational modification of lysine residues with the capacity for transcriptional regulation via histone modification and modulation of non-histone protein functions, which links gene regulation to cellular metabolism by aberrant metabolism activity and epigenetic modification. There is growing evidence that lactylation plays a crucial role in cancer progression and drug resistance. Targeting lactylation enzymes or metabolic pathways has shown promising effects in suppressing cancer progression and drug resistance, highlighting the therapeutic potential of this modification. Therefore, in this review, we offer a systematic overview of lactate homeostasis in physiological and pathological processes as well as discuss the influence of lactylation in cancer progression and drug resistance and underlying molecular mechanisms, providing a theoretical basis for further research.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101248"},"PeriodicalIF":15.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874194","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":"PARP inhibition elicits NK cell-associated immune evasion via potentiating HLA-G expression in tumor","authors":"Siyuan Wang ,&nbsp;Yu Xia ,&nbsp;Yiyu Qian ,&nbsp;Wen Pan ,&nbsp;Pu Huang ,&nbsp;Ning Jin ,&nbsp;Xin Li ,&nbsp;Cheng Xu ,&nbsp;Dan Liu ,&nbsp;Guangnian Zhao ,&nbsp;Yong Fang ,&nbsp;Christophe Nicot ,&nbsp;Qinglei Gao","doi":"10.1016/j.drup.2025.101247","DOIUrl":"10.1016/j.drup.2025.101247","url":null,"abstract":"<div><div>Resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) poses a significant challenge to enhancing the efficacy of cancer treatments. Beyond the cellular mechanisms intrinsic to tumor cells, the modulation of the tumor immune microenvironment is crucial in dictating the responsiveness to pharmacological interventions. Thus, there is a pressing need to elucidate the intricate interplay between PARPi and antitumor immune responses and to develop an optimized combinatorial therapeutic approach. In this study, using matched tumor samples before and after neoadjuvant monotherapy with the PARPi niraparib in a prospective clinical trial (NCT04507841), we observed a significant increase in natural killer (NK) cell infiltration post-treatment. However, this was not accompanied by the expected enhancement in their cytotoxic functions. This observation underscores the necessity to optimize the antitumor potential of NK cells by enhancing their cytotoxic capabilities. Upon exposure to niraparib, tumor cells, particularly those with wild-type EGFR, exhibited a pronounced upregulation of human leukocyte antigen G (HLA-G), an immune checkpoint impeding NK cell functions. Niraparib promotes EGFR internalization, which in turn diminishes AKT/mTOR signaling, leading to the increased transcriptional activity of the transcription factor EB (TFEB) and subsequent enhancement of HLA-G expression. The combination of niraparib with HLA-G blockade not only augmented NK cell-mediated tumor lysis <em>in vitro</em> but also synergistically inhibited tumor growth in humanized patient-derived xenograft models. Collectively, our results shed light on a previously unrecognized immune evasion mechanism and offer a compelling argument for the integration of HLA-G blockade with PARPi in cancer therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101247"},"PeriodicalIF":15.8,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906590","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":"MVP-LCN2 axis triggers evasion of ferroptosis to drive hepatocarcinogenesis and sorafenib resistance","authors":"Jiawen Xu ,&nbsp;Bo Wang ,&nbsp;Qiaoyu Liu ,&nbsp;Sheng Guo ,&nbsp;Chen Chen ,&nbsp;Jun Wu ,&nbsp;Xiaoya Zhao ,&nbsp;Mengmeng Li ,&nbsp;Zhuang Ma ,&nbsp;Shimeng Zhou ,&nbsp;Yun Qian ,&nbsp;Yijin Huang ,&nbsp;Zhangding Wang ,&nbsp;Chuanjun Shu ,&nbsp;Qingxiang Xu ,&nbsp;Jingjing Ben ,&nbsp;Qiang Wang ,&nbsp;Shouyu Wang","doi":"10.1016/j.drup.2025.101246","DOIUrl":"10.1016/j.drup.2025.101246","url":null,"abstract":"<div><div>RNA-binding proteins (RBPs) are critical regulators in tumorigenesis and therapy resistance by modulating RNA metabolism. However, the role of RBPs in hepatocarcinogenesis and progression remains elusive. Here, RBPs screening and integrating analyses identify major vault protein (MVP) as an oncogenic RBP in the occurrence of hepatocellular carcinoma (HCC) and sorafenib resistance via suppressing ferroptosis. Mechanistically, reactive oxygen species (ROS) induces STAT3-mediated MVP transcription activation and high expression in HCC cells. Subsequently, phosphoglycerate mutase family member 5 (PGAM5) directly dephosphorylates MVP at S873, facilitating its binding to the mRNA of iron-sequestering cytokine LCN2 and maintains its stability, thereby attenuating ferroptosis by reducing lipid peroxidation and intracellular Fe²⁺ content following sorafenib treatment. Notably, tenapanor, a potent pharmacological inhibitor of MVP, effectively disrupts the interaction between MVP and LCN2 mRNA and enhances ferroptosis and sorafenib sensitivity. Collectively, these findings underscore the central role of MVP in hepatocarcinogenesis and offer promising avenues to improve HCC treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101246"},"PeriodicalIF":15.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855147","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}