Pub Date : 2024-06-14DOI: 10.1016/j.drup.2024.101111
Kai-Lin Chen , Sai-Wei Huang , Ji-Jin Yao , Shi-Wei He , Sha Gong , Xi-Rong Tan , Ye-Lin Liang , Jun-Yan Li , Sheng-Yan Huang , Ying-Qin Li , Yin Zhao , Han Qiao , Sha Xu , Shengbing Zang , Jun Ma , Na Liu
Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.
{"title":"LncRNA DYNLRB2-AS1 promotes gemcitabine resistance of nasopharyngeal carcinoma by inhibiting the ubiquitination degradation of DHX9 protein","authors":"Kai-Lin Chen , Sai-Wei Huang , Ji-Jin Yao , Shi-Wei He , Sha Gong , Xi-Rong Tan , Ye-Lin Liang , Jun-Yan Li , Sheng-Yan Huang , Ying-Qin Li , Yin Zhao , Han Qiao , Sha Xu , Shengbing Zang , Jun Ma , Na Liu","doi":"10.1016/j.drup.2024.101111","DOIUrl":"10.1016/j.drup.2024.101111","url":null,"abstract":"<div><p>Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"76 ","pages":"Article 101111"},"PeriodicalIF":15.8,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141403928","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 : 2024-06-04DOI: 10.1016/j.drup.2024.101100
Ning Ji , Hui Li , Yixuan Zhang , Yuelin Li , Peiyu Wang , Xin Chen , Yi-Nan Liu , Jing-Quan Wang , Yuqi Yang , Zhe-Sheng Chen , Yueguo Li , Ran Wang , Dexin Kong
Aims
Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo.
Methods
Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo.
Results
Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2.
Conclusions
These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.
{"title":"Lansoprazole (LPZ) reverses multidrug resistance (MDR) in cancer through impeding ATP-binding cassette (ABC) transporter-mediated chemotherapeutic drug efflux and lysosomal sequestration","authors":"Ning Ji , Hui Li , Yixuan Zhang , Yuelin Li , Peiyu Wang , Xin Chen , Yi-Nan Liu , Jing-Quan Wang , Yuqi Yang , Zhe-Sheng Chen , Yueguo Li , Ran Wang , Dexin Kong","doi":"10.1016/j.drup.2024.101100","DOIUrl":"10.1016/j.drup.2024.101100","url":null,"abstract":"<div><h3>Aims</h3><p>Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, <em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Methods</h3><p>Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR <em>in vivo</em>.</p></div><div><h3>Results</h3><p>Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. <em>In vivo</em> experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2.</p></div><div><h3>Conclusions</h3><p>These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"76 ","pages":"Article 101100"},"PeriodicalIF":24.3,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141276541","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}
Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to evade anoikis, e.g. anoikis resistance, thereby allowing for cells to survive under anchorage-independent conditions. Uncovering the mechanisms of anoikis resistance will provide details about cancer metastasis, and potential strategies against cancer cell dissemination and metastasis. Here, we summarize the principal elements and core molecular mechanisms of anoikis and anoikis resistance. We discuss the latest progress of how anoikis and anoikis resistance are regulated in cancers. Furthermore, we summarize emerging data on selective compounds and nanomedicines, explaining how inhibiting anoikis resistance can serve as a meaningful treatment modality against cancers. Finally, we discuss the key limitations of this therapeutic paradigm and possible strategies to overcome them. In this review, we suggest that pharmacological modulation of anoikis and anoikis resistance by bioactive compounds could surmount anoikis resistance, highlighting a promising therapeutic regimen that could be used to overcome anoikis resistance in cancers.
{"title":"Targeting anoikis resistance as a strategy for cancer therapy","authors":"Yumin Wang , Sihang Cheng , Joshua S. Fleishman , Jichao Chen , Hailin Tang , Zhe-Sheng Chen , Wenkuan Chen , Mingchao Ding","doi":"10.1016/j.drup.2024.101099","DOIUrl":"10.1016/j.drup.2024.101099","url":null,"abstract":"<div><p>Anoikis, known as matrix detachment-induced apoptosis or detachment-induced cell death, is crucial for tissue development and homeostasis. Cancer cells develop means to evade anoikis, e.g. anoikis resistance, thereby allowing for cells to survive under anchorage-independent conditions. Uncovering the mechanisms of anoikis resistance will provide details about cancer metastasis, and potential strategies against cancer cell dissemination and metastasis. Here, we summarize the principal elements and core molecular mechanisms of anoikis and anoikis resistance. We discuss the latest progress of how anoikis and anoikis resistance are regulated in cancers. Furthermore, we summarize emerging data on selective compounds and nanomedicines, explaining how inhibiting anoikis resistance can serve as a meaningful treatment modality against cancers. Finally, we discuss the key limitations of this therapeutic paradigm and possible strategies to overcome them. In this review, we suggest that pharmacological modulation of anoikis and anoikis resistance by bioactive compounds could surmount anoikis resistance, highlighting a promising therapeutic regimen that could be used to overcome anoikis resistance in cancers.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"75 ","pages":"Article 101099"},"PeriodicalIF":24.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141232016","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 : 2024-06-01DOI: 10.1016/j.drup.2024.101098
Zhijie Xu , Haiyan Zhou , Tongfei Li , Qiaoli Yi , Abhimanyu Thakur , Kui Zhang , Xuelei Ma , Jiang-Jiang Qin , Yuanliang Yan
Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.
{"title":"Application of biomimetic nanovaccines in cancer immunotherapy: A useful strategy to help combat immunotherapy resistance","authors":"Zhijie Xu , Haiyan Zhou , Tongfei Li , Qiaoli Yi , Abhimanyu Thakur , Kui Zhang , Xuelei Ma , Jiang-Jiang Qin , Yuanliang Yan","doi":"10.1016/j.drup.2024.101098","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101098","url":null,"abstract":"<div><p>Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"75 ","pages":"Article 101098"},"PeriodicalIF":24.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141244735","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 : 2024-05-28DOI: 10.1016/j.drup.2024.101097
Jiatong Lin , Zejian Lyu , Huolun Feng , Huajie Xie , Jingwen Peng , Weifu Zhang , Jun Zheng , Jiabin Zheng , Zihao Pan , Yong Li
Although oxaliplatin (OXA) is widely used in the frontline treatment of colorectal cancer (CRC), CRC recurrence is commonly observed due to OXA resistance. OXA resistance is associated with a number of factors, including abnormal regulation of pyroptosis. It is therefore important to elucidate the abnormal regulatory mechanism underlying pyroptosis. Here, we identified that the circular RNA circPDIA3 played an important role in chemoresistance in CRC. CircPDIA3 could induce chemoresistance in CRC by inhibiting pyroptosis both in vitro and in vivo. Mechanistically, RIP, RNA pull-down and co-IP assays revealed that circPDIA3 directly bonded to the GSDME-C domain, subsequently enhanced the autoinhibitory effect of the GSDME-C domain through blocking the GSDME-C domain palmitoylation by ZDHHC3 and ZDHHC17, thereby restraining pyroptosis. Additionally, it was found that the circPDIA3/miR-449a/XBP1 positive feedback loop increased the expression of circPDIA3 to induce chemoresistance. Furthermore, our clinical data and patient-derived tumor xenograft (PDX) models supported the positive association of circPDIA3 with development of chemoresistance in CRC patients. Taken together, our findings demonstrated that circPDIA3 could promote chemoresistance by amplifying the autoinhibitory effect of the GSDME-C domain through inhibition of the GSDME-C domain palmitoylation in CRC. This study provides novel insights into the mechanism of circRNA in regulating pyroptosis and providing a potential therapeutic target for reversing chemoresistance of CRC.
{"title":"CircPDIA3/miR-449a/XBP1 feedback loop curbs pyroptosis by inhibiting palmitoylation of the GSDME-C domain to induce chemoresistance of colorectal cancer","authors":"Jiatong Lin , Zejian Lyu , Huolun Feng , Huajie Xie , Jingwen Peng , Weifu Zhang , Jun Zheng , Jiabin Zheng , Zihao Pan , Yong Li","doi":"10.1016/j.drup.2024.101097","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101097","url":null,"abstract":"<div><p>Although oxaliplatin (OXA) is widely used in the frontline treatment of colorectal cancer (CRC), CRC recurrence is commonly observed due to OXA resistance. OXA resistance is associated with a number of factors, including abnormal regulation of pyroptosis. It is therefore important to elucidate the abnormal regulatory mechanism underlying pyroptosis. Here, we identified that the circular RNA circPDIA3 played an important role in chemoresistance in CRC. CircPDIA3 could induce chemoresistance in CRC by inhibiting pyroptosis both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, RIP, RNA pull-down and co-IP assays revealed that circPDIA3 directly bonded to the GSDME-C domain, subsequently enhanced the autoinhibitory effect of the GSDME-C domain through blocking the GSDME-C domain palmitoylation by ZDHHC3 and ZDHHC17, thereby restraining pyroptosis. Additionally, it was found that the circPDIA3/miR-449a/XBP1 positive feedback loop increased the expression of circPDIA3 to induce chemoresistance. Furthermore, our clinical data and patient-derived tumor xenograft (PDX) models supported the positive association of circPDIA3 with development of chemoresistance in CRC patients. Taken together, our findings demonstrated that circPDIA3 could promote chemoresistance by amplifying the autoinhibitory effect of the GSDME-C domain through inhibition of the GSDME-C domain palmitoylation in CRC. This study provides novel insights into the mechanism of circRNA in regulating pyroptosis and providing a potential therapeutic target for reversing chemoresistance of CRC.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"76 ","pages":"Article 101097"},"PeriodicalIF":24.3,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000554/pdfft?md5=83c78ec039fe215f92b9afa7902bb535&pid=1-s2.0-S1368764624000554-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141303126","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}
Pub Date : 2024-05-27DOI: 10.1016/j.drup.2024.101096
Hao Zhang , Yujia Zheng , Zhen Wang , Lin Dong , Liyan Xue , Xiaolin Tian , Haiteng Deng , Qi Xue , Shugeng Gao , Yibo Gao , Chunxiang Li , Jie He
Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.
{"title":"KLF12 interacts with TRIM27 to affect cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma by regulating L1CAM expression","authors":"Hao Zhang , Yujia Zheng , Zhen Wang , Lin Dong , Liyan Xue , Xiaolin Tian , Haiteng Deng , Qi Xue , Shugeng Gao , Yibo Gao , Chunxiang Li , Jie He","doi":"10.1016/j.drup.2024.101096","DOIUrl":"10.1016/j.drup.2024.101096","url":null,"abstract":"<div><p>Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"76 ","pages":"Article 101096"},"PeriodicalIF":15.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000542/pdfft?md5=187095aa32767978e0fd5a94554e4ae8&pid=1-s2.0-S1368764624000542-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460569","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}
Pub Date : 2024-05-27DOI: 10.1016/j.drup.2024.101095
Haotian Cao , Tianjun Lan , Shijia Kuang , Liansheng Wang , Jintao Li , Qunxin Li , Yanyan Li , Qiuping Xu , Qian Chen , Shuwei Ren , Chunhong Lan , Nengtai Ouyang , Jianwei Liao , Yongsheng Huang , Jinsong Li
Background
Response to immunotherapy is the main challenge of head and neck squamous cancer (HNSCC) treatment. Previous studies have indicated that tumor mutational burden (TMB) is associated with prognosis, but it is not always a precise index. Hence, investigating specific genetic mutations and tumor microenvironment (TME) changes in TMB-high patients is essential for precision therapy of HNSCC.
Methods
A total of 33 HNSCC patients were enrolled in this study. We calculated the TMB score based on next-generation sequencing (NGS) sequencing and grouped these patients based on TMB score. Then, we examined the immune microenvironment of HNSCC using assessments of the bulk transcriptome and the single-cell RNA sequence (scRNA-seq) focusing on the molecular nature of TMB and mutations in HNSCC from our cohort. The association of the mutation pattern and TMB was analyzed in The Cancer Genome Atlas (TCGA) and validated by our cohort.
Results
33 HNSCC patients were divided into three groups (TMB-low, -medium, and -high) based on TMB score. In the result of 520-gene panel sequencing data, we found that FAT1 and LRP1B mutations were highly prevalent in TMB-high patients. FAT1 mutations are associated with resistance to immunotherapy in HNSCC patients. This involves many metabolism-related pathways like RERE, AIRE, HOMER1, etc. In the scRNA-seq data, regulatory T cells (Tregs), monocytes, and DCs were found mainly enriched in TMB-high samples.
Conclusion
Our analysis unraveled the FAT1 gene as an assistant predictor when we use TMB as a biomarker of drug resistance in HNSCC. Tregs, monocytes, and dendritic cells (DCs) were found mainly enriched in TMB-high samples.
{"title":"FAT1 as a tumor mutation burden specific gene affects the immunotherapy effect in head and neck squamous cell cancer","authors":"Haotian Cao , Tianjun Lan , Shijia Kuang , Liansheng Wang , Jintao Li , Qunxin Li , Yanyan Li , Qiuping Xu , Qian Chen , Shuwei Ren , Chunhong Lan , Nengtai Ouyang , Jianwei Liao , Yongsheng Huang , Jinsong Li","doi":"10.1016/j.drup.2024.101095","DOIUrl":"10.1016/j.drup.2024.101095","url":null,"abstract":"<div><h3>Background</h3><p>Response to immunotherapy is the main challenge of head and neck squamous cancer (HNSCC) treatment. Previous studies have indicated that tumor mutational burden (TMB) is associated with prognosis, but it is not always a precise index. Hence, investigating specific genetic mutations and tumor microenvironment (TME) changes in TMB-high patients is essential for precision therapy of HNSCC.</p></div><div><h3>Methods</h3><p>A total of 33 HNSCC patients were enrolled in this study. We calculated the TMB score based on next-generation sequencing (NGS) sequencing and grouped these patients based on TMB score. Then, we examined the immune microenvironment of HNSCC using assessments of the bulk transcriptome and the single-cell RNA sequence (scRNA-seq) focusing on the molecular nature of TMB and mutations in HNSCC from our cohort. The association of the mutation pattern and TMB was analyzed in The Cancer Genome Atlas (TCGA) and validated by our cohort.</p></div><div><h3>Results</h3><p>33 HNSCC patients were divided into three groups (TMB-low, -medium, and -high) based on TMB score. In the result of 520-gene panel sequencing data, we found that FAT1 and LRP1B mutations were highly prevalent in TMB-high patients. FAT1 mutations are associated with resistance to immunotherapy in HNSCC patients. This involves many metabolism-related pathways like RERE, AIRE, HOMER1, etc. In the scRNA-seq data, regulatory T cells (Tregs), monocytes, and DCs were found mainly enriched in TMB-high samples.</p></div><div><h3>Conclusion</h3><p>Our analysis unraveled the FAT1 gene as an assistant predictor when we use TMB as a biomarker of drug resistance in HNSCC. Tregs, monocytes, and dendritic cells (DCs) were found mainly enriched in TMB-high samples.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"76 ","pages":"Article 101095"},"PeriodicalIF":15.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141581475","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 : 2024-04-26DOI: 10.1016/j.drup.2024.101088
Yating Guo , Geng Zou , Anusak Kerdsin , Constance Schultsz , Can Hu , Weicheng Bei , Huanchun Chen , Jinquan Li , Yang Zhou
In this study, the progenitors of MCR-3, MCR-7 and MCR-5, namely NMCR-3, NMCR-4 and NMCR-5, were firstly discovered and indicating Aeromonas was a natural reservoir for MCR-3 and MCR-7. Furthermore, different evolutionary models for MCR-3, MCR-7 and MCR-5 were proposed.
{"title":"Characterization of NMCR-3, NMCR-4 and NMCR-5, three novel non-mobile colistin resistance determinants: Implications for MCR-3, MCR-7, and MCR-5 progenitors, respectively","authors":"Yating Guo , Geng Zou , Anusak Kerdsin , Constance Schultsz , Can Hu , Weicheng Bei , Huanchun Chen , Jinquan Li , Yang Zhou","doi":"10.1016/j.drup.2024.101088","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101088","url":null,"abstract":"<div><p>In this study, the progenitors of MCR-3, MCR-7 and MCR-5, namely NMCR-3, NMCR-4 and NMCR-5, were firstly discovered and indicating <em>Aeromonas</em> was a natural reservoir for MCR-3 and MCR-7. Furthermore, different evolutionary models for MCR-3, MCR-7 and MCR-5 were proposed.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"75 ","pages":"Article 101088"},"PeriodicalIF":24.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000463/pdfft?md5=c9ed71f1b7ae173d499d611ebb7b61a1&pid=1-s2.0-S1368764624000463-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140913941","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}
Pub Date : 2024-04-23DOI: 10.1016/j.drup.2024.101086
Mingxia Jiang , Qiao Li , Binghe Xu
Antibody-drug conjugates (ADCs) represent a novel and promising approach in targeted therapy, uniting the specificity of antibodies that recognize specific antigens with payloads, all connected by the stable linker. These conjugates combine the best targeted and cytotoxic therapies, offering the killing effect of precisely targeting specific antigens and the potent cell-killing power of small molecule drugs. The targeted approach minimizes the off-target toxicities associated with the payloads and broadens the therapeutic window, enhancing the efficacy and safety profile of cancer treatments. Within precision oncology, ADCs have garnered significant attention as a cutting-edge research area and have been approved to treat a range of malignant tumors. Correspondingly, the issue of resistance to ADCs has gradually come to the fore. Any dysfunction in the steps leading to the ADCs' action within tumor cells can lead to the development of resistance. A deeper understanding of resistance mechanisms may be crucial for developing novel ADCs and exploring combination therapy strategies, which could further enhance the clinical efficacy of ADCs in cancer treatment. This review outlines the brief historical development and mechanism of ADCs and discusses the impact of their key components on the activity of ADCs. Furthermore, it provides a detailed account of the application of ADCs with various target antigens in cancer therapy, the categorization of potential resistance mechanisms, and the current state of combination therapies. Looking forward, breakthroughs in overcoming technical barriers, selecting differentiated target antigens, and enhancing resistance management and combination therapy strategies will broaden the therapeutic indications for ADCs. These progresses are anticipated to advance cancer treatment and yield benefits for patients.
{"title":"Spotlight on ideal target antigens and resistance in antibody-drug conjugates: Strategies for competitive advancement","authors":"Mingxia Jiang , Qiao Li , Binghe Xu","doi":"10.1016/j.drup.2024.101086","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101086","url":null,"abstract":"<div><p>Antibody-drug conjugates (ADCs) represent a novel and promising approach in targeted therapy, uniting the specificity of antibodies that recognize specific antigens with payloads, all connected by the stable linker. These conjugates combine the best targeted and cytotoxic therapies, offering the killing effect of precisely targeting specific antigens and the potent cell-killing power of small molecule drugs. The targeted approach minimizes the off-target toxicities associated with the payloads and broadens the therapeutic window, enhancing the efficacy and safety profile of cancer treatments. Within precision oncology, ADCs have garnered significant attention as a cutting-edge research area and have been approved to treat a range of malignant tumors. Correspondingly, the issue of resistance to ADCs has gradually come to the fore. Any dysfunction in the steps leading to the ADCs' action within tumor cells can lead to the development of resistance. A deeper understanding of resistance mechanisms may be crucial for developing novel ADCs and exploring combination therapy strategies, which could further enhance the clinical efficacy of ADCs in cancer treatment. This review outlines the brief historical development and mechanism of ADCs and discusses the impact of their key components on the activity of ADCs. Furthermore, it provides a detailed account of the application of ADCs with various target antigens in cancer therapy, the categorization of potential resistance mechanisms, and the current state of combination therapies. Looking forward, breakthroughs in overcoming technical barriers, selecting differentiated target antigens, and enhancing resistance management and combination therapy strategies will broaden the therapeutic indications for ADCs. These progresses are anticipated to advance cancer treatment and yield benefits for patients.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"75 ","pages":"Article 101086"},"PeriodicalIF":24.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140645896","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 : 2024-04-23DOI: 10.1016/j.drup.2024.101087
Sara Diaz-Diaz , Andrea Garcia-Montaner , Roberta Vanni , Marina Murillo-Torres , Esther Recacha , Marina R. Pulido , Maria Romero-Muñoz , Fernando Docobo-Pérez , Alvaro Pascual , Jose Manuel Rodriguez-Martinez
In recent years, new evidence has shown that the SOS response plays an important role in the response to antimicrobials, with involvement in the generation of clinical resistance. Here we evaluate the impact of heterogeneous expression of the SOS response in clinical isolates of Escherichia coli on response to the fluoroquinolone, ciprofloxacin. In silico analysis of whole genome sequencing data showed remarkable sequence conservation of the SOS response regulators, RecA and LexA. Despite the genetic homogeneity, our results revealed a marked differential heterogeneity in SOS response activation, both at population and single-cell level, among clinical isolates of E. coli in the presence of subinhibitory concentrations of ciprofloxacin. Four main stages of SOS response activation were identified and correlated with cell filamentation. Interestingly, there was a correlation between clinical isolates with higher expression of the SOS response and further progression to resistance. This heterogeneity in response to DNA damage repair (mediated by the SOS response) and induced by antimicrobial agents could be a new factor with implications for bacterial evolution and survival contributing to the generation of antimicrobial resistance.
近年来,新的证据表明,SOS 反应在抗菌药物反应中发挥着重要作用,并参与了临床耐药性的产生。在此,我们评估了大肠埃希菌临床分离株中 SOS 反应异质性表达对氟喹诺酮类药物环丙沙星反应的影响。对全基因组测序数据的硅学分析表明,SOS 响应调节因子 RecA 和 LexA 的序列具有显著的保守性。尽管基因具有同质性,但我们的研究结果表明,在亚抑制浓度环丙沙星的作用下,临床分离的大肠杆菌在群体和单细胞水平上的 SOS 反应激活具有明显的差异性。确定了 SOS 反应激活的四个主要阶段,并将其与细胞丝状化相关联。有趣的是,SOS 反应表达较高的临床分离株与耐药性的进一步发展之间存在相关性。这种由抗菌剂诱导的 DNA 损伤修复反应(由 SOS 反应介导)的异质性可能是对细菌进化和生存产生影响的一个新因素,有助于抗菌剂耐药性的产生。
{"title":"Heterogeneity of SOS response expression in clinical isolates of Escherichia coli influences adaptation to antimicrobial stress","authors":"Sara Diaz-Diaz , Andrea Garcia-Montaner , Roberta Vanni , Marina Murillo-Torres , Esther Recacha , Marina R. Pulido , Maria Romero-Muñoz , Fernando Docobo-Pérez , Alvaro Pascual , Jose Manuel Rodriguez-Martinez","doi":"10.1016/j.drup.2024.101087","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101087","url":null,"abstract":"<div><p>In recent years, new evidence has shown that the SOS response plays an important role in the response to antimicrobials, with involvement in the generation of clinical resistance. Here we evaluate the impact of heterogeneous expression of the SOS response in clinical isolates of <em>Escherichia coli</em> on response to the fluoroquinolone, ciprofloxacin. <em>In silico</em> analysis of whole genome sequencing data showed remarkable sequence conservation of the SOS response regulators, RecA and LexA. Despite the genetic homogeneity, our results revealed a marked differential heterogeneity in SOS response activation, both at population and single-cell level, among clinical isolates of <em>E. coli</em> in the presence of subinhibitory concentrations of ciprofloxacin. Four main stages of SOS response activation were identified and correlated with cell filamentation. Interestingly, there was a correlation between clinical isolates with higher expression of the SOS response and further progression to resistance. This heterogeneity in response to DNA damage repair (mediated by the SOS response) and induced by antimicrobial agents could be a new factor with implications for bacterial evolution and survival contributing to the generation of antimicrobial resistance.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"75 ","pages":"Article 101087"},"PeriodicalIF":24.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000451/pdfft?md5=d62973c9569c8b14b7be721203fa08fd&pid=1-s2.0-S1368764624000451-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140650582","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}