Drug Resistance Updates最新文献

{"title":"Widespread loss-of-function mutations implicating preexisting resistance to new or repurposed anti-tuberculosis drugs","authors":"Derek Conkle-Gutierrez,&nbsp;Bria M. Gorman,&nbsp;Nachiket Thosar,&nbsp;Afif Elghraoui,&nbsp;Samuel J. Modlin,&nbsp;Faramarz Valafar","doi":"10.1016/j.drup.2024.101156","DOIUrl":"10.1016/j.drup.2024.101156","url":null,"abstract":"<div><h3>Background</h3><div>Five New or Repurposed Drugs (NRDs) were approved in the last decade for treatment of multi-drug resistant tuberculosis: bedaquiline, clofazimine, linezolid, delamanid, and pretomanid. Unfortunately, resistance to these drugs emerged faster than anticipated, potentially due to preexisting resistance in naïve strains. Previous investigations into the rapid emergence have mostly included short variants. For the first time, we utilize <em>de novo</em>-assembled genomes, and systematically include Structural Variations (SV) and heterogeneity to comprehensively study this rapid emergence. We show high prevalence of preexisting resistance, identify novel markers of resistance, and lay the foundation for preventing preexisting resistance in future drug development.</div></div><div><h3>Methods</h3><div>First, a systematic literature review revealed 313 NRD resistance variants in 13 genes. Next, 409 globally diverse clinical isolates collected prior to the drugs’ programmatic use (308 were multidrug resistant, 106 had <em>de novo</em> assembled genomes) were utilized to study the 13 genes comprehensively for conventional, structural, and heterogeneous variants.</div></div><div><h3>Findings</h3><div>We identified 5 previously reported and 67 novel putative NRD resistance variants. These variants were 2 promoter mutations (in 8/409 isolates), 13 frameshifts (21/409), 6 SVs (9/409), 35 heterogeneous frameshifts (32/409) and 11 heterogeneous SVs (12/106). Delamanid and pretomanid resistance mutations were most prevalent (48/409), while linezolid resistance mutations were least prevalent (8/409).</div></div><div><h3>Interpretation</h3><div>Preexisting mutations implicated in resistance to at least one NRD was highly prevalent (85/409, 21 %). This was mostly caused by loss-of-function mutations in genes responsible for prodrug activation and efflux pump regulation. These preexisting mutations may have emerged through a bet-hedging strategy, or through cross-resistance with non-tuberculosis drugs such as metronidazole. Future drugs that could be resisted through loss-of-function in non-essential genes may suffer from preexisting resistance. The methods used here for comprehensive preexisting resistance assessment (especially SVs and heterogeneity) may mitigate this risk during early-stage drug development.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101156"},"PeriodicalIF":15.8,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer","authors":"Zhuang Liu ,&nbsp;Chang Liu ,&nbsp;Caihong Fan ,&nbsp;Runze Li ,&nbsp;Shiqi Zhang ,&nbsp;Jia Liu ,&nbsp;Bo Li ,&nbsp;Shengzheng Zhang ,&nbsp;Lihong Guo ,&nbsp;Xudong Wang ,&nbsp;Zhi Qi ,&nbsp;Yanna Shen","doi":"10.1016/j.drup.2024.101154","DOIUrl":"10.1016/j.drup.2024.101154","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) remains the foremost contributor to cancer-related fatalities globally, with limited effective therapeutic modalities. Recent research has shed light on the role of ferroptosis in various types of cancers, offering a potential avenue for improving cancer therapy. Herein, we identified E3 ubiquitin ligase deltex 2 (DTX2) as a potential therapeutic target candidate implicated in promoting NSCLC cell growth by inhibiting ferroptosis. Our investigation revealed a significant upregulation of DTX2 in NSCLC cells and tissues, which was correlated with poor prognosis. Downregulation of DTX2 suppressed NSCLC cell growth both <em>in vitro</em> and <em>in vivo</em>, while its overexpression accelerated cell proliferation. Moreover, knockdown of DTX2 promoted ferroptosis in NSCLC cells, which was mitigated by DTX2 overexpression. Mechanistically, we uncovered that DTX2 binds to nuclear receptor coactivator 4 (NCOA4), facilitating its ubiquitination and degradation via the K48 chain, which subsequently dampens NCOA4-driven ferritinophagy and ferroptosis in NSCLC cells. Notably, DTX2 knockdown promotes cisplatin-induced ferroptosis and overcomes drug resistance of NSCLC cells. These findings underscore the critical role of DTX2 in regulating ferroptosis and NCOA4-mediated ferritinophagy, suggesting its potential as a novel therapeutic target for NSCLC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101154"},"PeriodicalIF":15.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376191","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":"Breaking the barrier: Epigenetic strategies to combat platinum resistance in colorectal cancer","authors":"Shiwen Luo ,&nbsp;Ming Yue ,&nbsp;Dequan Wang ,&nbsp;Yukang Lu ,&nbsp;Qingming Wu ,&nbsp;Jue Jiang","doi":"10.1016/j.drup.2024.101152","DOIUrl":"10.1016/j.drup.2024.101152","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Platinum-based drugs, such as cisplatin and oxaliplatin, are frontline chemotherapy for CRC, effective in both monotherapy and combination regimens. However, the clinical efficacy of these treatments is often undermined by the development of drug resistance, a significant obstacle in cancer therapy. In recent years, epigenetic alterations have been recognized as key players in the acquisition of resistance to platinum drugs. Targeting these dysregulated epigenetic mechanisms with small molecules represents a promising therapeutic strategy. This review explores the complex relationship between epigenetic changes and platinum resistance in CRC, highlighting current epigenetic therapies and their effectiveness in countering resistance mechanisms. By elucidating the epigenetic underpinnings of platinum resistance, this review aims to contribute to ongoing efforts to improve treatment outcomes for CRC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101152"},"PeriodicalIF":15.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prophylactic use of antibiotics – A strategy with unforeseen risks?","authors":"Jan Rupp ,&nbsp;Claudia Bozzaro ,&nbsp;Hinrich Schulenburg","doi":"10.1016/j.drup.2024.101155","DOIUrl":"10.1016/j.drup.2024.101155","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101155"},"PeriodicalIF":15.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergence of novel Klebsiella pneumoniae ST types with multidrug resistance in clinic","authors":"Zhenghao Lou ,&nbsp;Xiaolu Yang ,&nbsp;Yu Yang,&nbsp;Kexin Guo,&nbsp;Lu Gong,&nbsp;Hao Xu,&nbsp;Beiwen Zheng,&nbsp;Wenhong Liu,&nbsp;Mantao Chen,&nbsp;Xiawei Jiang","doi":"10.1016/j.drup.2024.101153","DOIUrl":"10.1016/j.drup.2024.101153","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101153"},"PeriodicalIF":15.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320124","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":"O-GlcNAcylation regulation of RIPK1-dependent apoptosis dictates sensitivity to sunitinib in renal cell carcinoma","authors":"Xiangbo Zeng ,&nbsp;Zhiliang Chen ,&nbsp;Yuanchao Zhu ,&nbsp;Lei Liu ,&nbsp;Zhiyong Zhang ,&nbsp;Yongyuan Xiao ,&nbsp;Qiong Wang ,&nbsp;Shiyu Pang ,&nbsp;Fengjin Zhao ,&nbsp;Bihong Xu ,&nbsp;Mengxin Leng ,&nbsp;Xiaocen Liu ,&nbsp;Chenxi Hu ,&nbsp;Siying Zeng ,&nbsp;Fei Li ,&nbsp;Wenlian Xie ,&nbsp;Wanlong Tan ,&nbsp;Zaosong Zheng","doi":"10.1016/j.drup.2024.101150","DOIUrl":"10.1016/j.drup.2024.101150","url":null,"abstract":"<div><p>Receptor interacting protein kinase 1 (RIPK1) has emerged as a key regulatory molecule that influences the balance between cell death and cell survival. Under external stress, RIPK1 determines whether a cell undergoes RIPK-dependent apoptosis (RDA) or survives by activating NF-κB signaling. However, the role and mechanisms of RIPK1 on sunitinib sensitivity in renal cell carcinoma (RCC) remain elusive. In this study, we demonstrated that the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of RIPK1 induces sunitinib resistance in RCC by inhibiting RDA. O-GlcNAc transferase (OGT) specifically interacts with RIPK1 through its tetratricopeptide repeats (TPR) domain and facilitates RIPK1 O-GlcNAcylation. The O-GlcNAcylation of RIPK1 at Ser³³¹, Ser⁴⁴⁰ and Ser⁶⁶⁹ regulates RIPK1 ubiquitination and the formation of the RIPK1/FADD/Caspase-8 complex, thereby inhibiting sunitinib-induced RDA in RCC. Site-specific depletion of O-GlcNAcylation on RIPK1 affects the formation of the RIPK1/FADD/Caspase 8 complex, leading to increased sunitinib sensitivity in RCC.</p><p>Our data highlight the significance of aberrant RIPK1 O-GlcNAcylation in the development of sunitinib resistance and indicate that targeting RIPK1 O-GlcNAcylation could be a promising therapeutic strategy for RCC.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101150"},"PeriodicalIF":15.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142228809","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":"CYP1B1 promotes PARPi-resistance via histone H1.4 interaction and increased chromatin accessibility in ovarian cancer","authors":"Yite Xue ,&nbsp;Taotao Yin ,&nbsp;Shuo Yuan ,&nbsp;Lingfang Wang ,&nbsp;Hui Lin ,&nbsp;Tianzhe Jin ,&nbsp;Ruiyi Xu ,&nbsp;Jiaxin Gu ,&nbsp;Shizhen Shen ,&nbsp;Xiaojing Chen ,&nbsp;Zhuoye Chen ,&nbsp;Ni Sima ,&nbsp;Lifeng Chen ,&nbsp;Weiguo Lu ,&nbsp;Xiao Li ,&nbsp;Xiaodong Cheng ,&nbsp;Hui Wang","doi":"10.1016/j.drup.2024.101151","DOIUrl":"10.1016/j.drup.2024.101151","url":null,"abstract":"<div><h3>Introduction</h3><div>Ovarian cancer is the most lethal gynecological cancer and presents significant therapeutic challenges. The discovery of synthetic lethality between PARP inhibitors (PARPi) and homologous recombination deficiency marked a new era in treating BRCA1/2-mutated tumors. However, PARPi resistance remains a major clinical challenge.</div></div><div><h3>Methods</h3><div>RNA sequencing was used to identify genes altered by PARPi treatment and LC-MS was used to detect proteins interacting with CYP1B1. Resistance mechanisms were explored through ATAC-seq and gene expression manipulation. Additional techniques, including micrococcal nuclease digestion assays, DAPI staining, and fluorescence microscopy, were used to assess changes in nuclear morphology and chromatin accessibility.</div></div><div><h3>Results</h3><div>The gradual exposure of Olaparib has developed a PARPi-resistant cell line, A2780-OlaR, which exhibits significant upregulation of CYP1B1 at both RNA and protein levels. Down-regulating CYP1B1 expression or using specific inhibitors decreased the cellular response to Olaparib. Linker histone H1.4 was identified as associated with CYP1B1. ATAC-seq showed differential chromatin accessibility between A2780-OlaR and parental cells, indicating that the downregulation of H1.4 was associated with increased chromatin accessibility and higher cell viability after Olaparib treatment.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a novel role for CYP1B1 in driving PARPi resistance through distinct molecular mechanisms in A2780-OlaR. This study highlights the importance of chromatin accessibility in PARPi efficacy and suggests the CYP1B1/H1.4 axis as a promising therapeutic target for overcoming drug resistance in ovarian cancer, offering potentially therapeutic benefits.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101151"},"PeriodicalIF":15.8,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142416322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The important role of lactylation in regulating DNA damage repair and tumor chemotherapy resistance","authors":"Jia Li, Zhe-Sheng Chen, Yihang Pan, Leli Zeng","doi":"10.1016/j.drup.2024.101148","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101148","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"3 1","pages":"101148"},"PeriodicalIF":24.3,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142233567","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":"RGS5+ lymphatic endothelial cells facilitate metastasis and acquired drug resistance of breast cancer through oxidative stress-sensing mechanism","authors":"Caixin Qiu ,&nbsp;Chaoyi Tang ,&nbsp;Yujun Tang ,&nbsp;Ka Su ,&nbsp;Xiao Chai ,&nbsp;Zexu Zhan ,&nbsp;Xing Niu ,&nbsp;Jiehua Li","doi":"10.1016/j.drup.2024.101149","DOIUrl":"10.1016/j.drup.2024.101149","url":null,"abstract":"<div><h3>Aims</h3><div>Oxidative stress reflected by elevated reactive oxygen species (ROS) in the tumor ecosystem, is a hallmark of human cancers. The mechanisms by which oxidative stress regulate the metastatic ecosystem and resistance remain elusive. This study aimed to dissect the oxidative stress-sensing machinery during the evolvement of early dissemination and acquired drug resistance in breast cancer.</div></div><div><h3>Methods</h3><div>Here, we constructed single-cell landscape of primary breast tumors and metastatic lymph nodes, and focused on RGS5⁺ endothelial cell subpopulation in breast cancer metastasis and resistance.</div></div><div><h3>Results</h3><div>We reported on RGS5 as a master in endothelial cells sensing oxidative stress. RGS5⁺ endothelial cells facilitated tumor-endothelial adhesion and transendothelial migration of breast cancer cells. Antioxidant suppressed oxidative stress-induced RGS5 expression in endothelial cells, and prevented adhesion and transendothelial migration of cancer cells. RGS5-overexpressed HLECs displayed attenuated glycolysis and oxidative phosphorylation. Drug-resistant HLECs with RGS5 overexpression conferred acquired drug resistance of breast cancer cells. Importantly, genetic knockdown of RGS5 prevented tumor growth and lymph node metastasis.</div></div><div><h3>Conclusions</h3><div>Our work demonstrates that RGS5 in lymphatic endothelial cells senses oxidative stress to promote breast cancer lymph node metastasis and resistance, providing a novel insight into a potentially targetable oxidative stress-sensing machinery in breast cancer treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101149"},"PeriodicalIF":15.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275811","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":"Plasmid-borne tigecycline resistance gene tet(X4) in Salmonella enterica and Escherichia coli isolates from a pediatric patient with diarrhea","authors":"Zelin Yan ,&nbsp;Yan Li ,&nbsp;Yingling Ni,&nbsp;Xiaoni Xia,&nbsp;Yanyan Zhang,&nbsp;Yuchen Wu,&nbsp;Jing Zhang,&nbsp;Gongxiang Chen,&nbsp;Ruichao Li,&nbsp;Rong Zhang","doi":"10.1016/j.drup.2024.101145","DOIUrl":"10.1016/j.drup.2024.101145","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"77 ","pages":"Article 101145"},"PeriodicalIF":15.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122726","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}