Pub Date : 2025-01-25DOI: 10.1016/j.drup.2025.101205
Xi Li , Longjie Zhou , Huaqiong Huang
The molecular mechanisms driving the development of KPC-230-mediated resistance to ceftazidime-avibactam during treatment of carbapenem-resistant Klebsiella pneumoniae infection was elucidated by analyzing specimens collected from a patient, including one blaKPC-230-positive and three blaKPC-2-positive Klebsiella pnenmoniae isolates.
{"title":"Dynamic evolution of KPC-230-mediated resistance to ceftazidime-avibactam during the treatment of carbapenem-resistant Klebsiella pnenmoniae","authors":"Xi Li , Longjie Zhou , Huaqiong Huang","doi":"10.1016/j.drup.2025.101205","DOIUrl":"10.1016/j.drup.2025.101205","url":null,"abstract":"<div><div>The molecular mechanisms driving the development of KPC-230-mediated resistance to ceftazidime-avibactam during treatment of carbapenem-resistant <em>Klebsiella pneumoniae</em> infection was elucidated by analyzing specimens collected from a patient, including one <em>bla</em><sub>KPC-230</sub>-positive and three <em>bla</em><sub>KPC-2</sub>-positive <em>Klebsiella pnenmoniae</em> isolates<em>.</em></div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101205"},"PeriodicalIF":15.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076041","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}
The aquatic environment is a major pathway for the spread of antibiotic resistance (AR) among microorganisms. Among these, Klebsiella pneumoniae reveals high genome plasticity, adaptability, and the ability to colonize humans, animals, and the natural environment, awarding it a significant role in the spread of AR. This work presents an in-depth analysis of the whole sequences of 149 K. pneumoniae genomes isolated from surface waters available in databases. The sequences were obtained from 20 countries in five continents. The analyses showed a high genomic diversity of isolates, classifying them into 94 unique sequence types. The isolates carried numerous virulence and drug resistance determinants in their genomes, including genes for carbapenem and colistin resistance. The critical resistance genes were located on plasmids, indicating their high mobility and ease of access in water environments. Sublineage 258 members, in particular ST11, have been identified as important carriers of both important drug resistance determinants and key virulence factors, thus posing a substantial threat to human health. Our analysis revealed the direct transmission of drug-resistant and virulent clinical strains to the natural environment, highlighting the role of K. pneumoniae in the dissemination of drug resistance within the "One Health" framework. Surface waters represent an environment conducive to the spread and evolution of drug resistance, and K. pneumoniae plays a significant role in this process by providing clinically-significant antibiotic resistance genes to environmental recipients.
{"title":"Global dissemination of Klebsiella pneumoniae in surface waters: Genomic insights into drug resistance, virulence, and clinical relevance","authors":"Damian Rolbiecki , Edyta Kiedrzyńska , Małgorzata Czatzkowska , Marcin Kiedrzyński , Ewa Korzeniewska , Monika Harnisz","doi":"10.1016/j.drup.2025.101204","DOIUrl":"10.1016/j.drup.2025.101204","url":null,"abstract":"<div><div>The aquatic environment is a major pathway for the spread of antibiotic resistance (AR) among microorganisms. Among these, <em>Klebsiella pneumoniae</em> reveals high genome plasticity, adaptability, and the ability to colonize humans, animals, and the natural environment, awarding it a significant role in the spread of AR. This work presents an in-depth analysis of the whole sequences of 149 <em>K. pneumoniae</em> genomes isolated from surface waters available in databases. The sequences were obtained from 20 countries in five continents. The analyses showed a high genomic diversity of isolates, classifying them into 94 unique sequence types. The isolates carried numerous virulence and drug resistance determinants in their genomes, including genes for carbapenem and colistin resistance. The critical resistance genes were located on plasmids, indicating their high mobility and ease of access in water environments. Sublineage 258 members, in particular ST11, have been identified as important carriers of both important drug resistance determinants and key virulence factors, thus posing a substantial threat to human health. Our analysis revealed the direct transmission of drug-resistant and virulent clinical strains to the natural environment, highlighting the role of <em>K. pneumoniae</em> in the dissemination of drug resistance within the \"One Health\" framework. Surface waters represent an environment conducive to the spread and evolution of drug resistance, and <em>K. pneumoniae</em> plays a significant role in this process by providing clinically-significant antibiotic resistance genes to environmental recipients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101204"},"PeriodicalIF":15.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030248","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 : 2025-01-18DOI: 10.1016/j.drup.2025.101203
Ana Monfort-Vengut , Natalia Sanz-Gómez , Sandra Ballesteros-Sánchez , Beatriz Ortigosa , Aitana Cambón , Maria Ramos , Ángela Montes-San Lorenzo , María Escribano-Cebrián , Juan Manuel Rosa-Rosa , Joaquín Martínez-López , Ricardo Sánchez-Prieto , Rocío Sotillo , Guillermo de Cárcer
Ion homeostasis is critical for numerous cellular processes, and disturbances in ionic balance underlie diverse pathological conditions, including cancer progression. Targeting ion homeostasis is even considered as a strategy to treat cancer. However, very little is known about how ion homeostasis may influence anticancer drug response. In a genome-wide CRISPR-Cas9 resistance drug screen, we identified and validated the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic inhibitor rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib treatment but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these compounds. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing compounds, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as an important modulator for microtubule-associated chemotherapy response.
{"title":"Osmotic stress influences microtubule drug response via WNK1 kinase signaling","authors":"Ana Monfort-Vengut , Natalia Sanz-Gómez , Sandra Ballesteros-Sánchez , Beatriz Ortigosa , Aitana Cambón , Maria Ramos , Ángela Montes-San Lorenzo , María Escribano-Cebrián , Juan Manuel Rosa-Rosa , Joaquín Martínez-López , Ricardo Sánchez-Prieto , Rocío Sotillo , Guillermo de Cárcer","doi":"10.1016/j.drup.2025.101203","DOIUrl":"10.1016/j.drup.2025.101203","url":null,"abstract":"<div><div>Ion homeostasis is critical for numerous cellular processes, and disturbances in ionic balance underlie diverse pathological conditions, including cancer progression. Targeting ion homeostasis is even considered as a strategy to treat cancer. However, very little is known about how ion homeostasis may influence anticancer drug response. In a genome-wide CRISPR-Cas9 resistance drug screen, we identified and validated the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic inhibitor rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib treatment but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these compounds. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing compounds, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as an important modulator for microtubule-associated chemotherapy response.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101203"},"PeriodicalIF":15.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035184","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 : 2025-01-09DOI: 10.1016/j.drup.2025.101202
Yong Wang , Zhiguo Liu , Yang Li , Kelin Wang , Chunhui Yuan , Jian Shi , Jiazhong Ren , Shijie Wang , Jinping Wang , Miaoqing Zhao , Man Hu
Radioresistance remains a great challenge for radiotherapy in the treatment of glioblastoma (GBM). PD-L1 expression is a key contributor to radioresistance and immune escape in GBM. The lack of effective methods to monitor the change of PD-L1 during radiotherapy in patients limits timely intervention and management of the resistance. Here, we developed a novel peptide tracer [18F]AlF-NOTA-PCP2 for PET/CT to visualize the changes of PD-L1 expression in response to radiotherapy, revealing PD-L1-driven radioresistance in GBM. The [18F]AlF-NOTA-PCP2 demonstrated high specificity and binding affinity to PD-L1 in vitro. The uptake of [18F]AlF-NOTA-PCP2 on PET/CT showed a strong positive correlation with PD-L1 expression by immunohistochemistry (IHC) (R² = 0.861, P < 0.001) in GBM xenograft tumors. The radiotracer uptake in PD-L1-positive tumors significantly increased post-radiotherapy (21.25 ± 0.91 % vs. 25.12 ± 0.82 %, P = 0.008), aligning with the radioresistance observed in these tumors. In vitro studies revealed that PD-L1-driven radioresistance by enhancing DNA damage repair through upregulation of RAD51 after activation of the PI3K-Akt pathway in cells. Preliminary clinical application in a radiotherapy-treated GBM patient demonstrated the ability to monitor PD-L1 dynamics, supporting its potential for clinical translation. Collectively, this peptide-based small molecule PET/CT radiotracers offer a noninvasive, real-time, and quantitative method to dynamically visualize PD-L1-driven radioresistance in GBM. It could serve as a potential radiotracer for facilitating patient stratification, adjusting radiotherapy regimens, and guiding personalized immunotherapy strategies.
{"title":"Peptide-based PET/CT imaging visualizes PD-L1-driven radioresistance in glioblastoma","authors":"Yong Wang , Zhiguo Liu , Yang Li , Kelin Wang , Chunhui Yuan , Jian Shi , Jiazhong Ren , Shijie Wang , Jinping Wang , Miaoqing Zhao , Man Hu","doi":"10.1016/j.drup.2025.101202","DOIUrl":"10.1016/j.drup.2025.101202","url":null,"abstract":"<div><div>Radioresistance remains a great challenge for radiotherapy in the treatment of glioblastoma (GBM). PD-L1 expression is a key contributor to radioresistance and immune escape in GBM. The lack of effective methods to monitor the change of PD-L1 during radiotherapy in patients limits timely intervention and management of the resistance. Here, we developed a novel peptide tracer [<sup>18</sup>F]AlF-NOTA-PCP2 for PET/CT to visualize the changes of PD-L1 expression in response to radiotherapy, revealing PD-L1-driven radioresistance in GBM. The [<sup>18</sup>F]AlF-NOTA-PCP2 demonstrated high specificity and binding affinity to PD-L1 <em>in vitro.</em> The uptake of [<sup>18</sup>F]AlF-NOTA-PCP2 on PET/CT showed a strong positive correlation with PD-L1 expression by immunohistochemistry (IHC) (<em>R</em>² = 0.861, <em>P</em> < 0.001) in GBM xenograft tumors. The radiotracer uptake in PD-L1-positive tumors significantly increased post-radiotherapy (21.25 ± 0.91 % vs. 25.12 ± 0.82 %, <em>P</em> = 0.008), aligning with the radioresistance observed in these tumors. <em>In vitro</em> studies revealed that PD-L1-driven radioresistance by enhancing DNA damage repair through upregulation of RAD51 after activation of the PI3K-Akt pathway in cells. Preliminary clinical application in a radiotherapy-treated GBM patient demonstrated the ability to monitor PD-L1 dynamics, supporting its potential for clinical translation. Collectively, this peptide-based small molecule PET/CT radiotracers offer a noninvasive, real-time, and quantitative method to dynamically visualize PD-L1-driven radioresistance in GBM. It could serve as a potential radiotracer for facilitating patient stratification, adjusting radiotherapy regimens, and guiding personalized immunotherapy strategies.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101202"},"PeriodicalIF":15.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990351","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 : 2025-01-07DOI: 10.1016/j.drup.2025.101201
Kuan Li , Wenchao Li , Shuying Fu , Chen Wang , Kexin Wang , Huan Yang , Yumei Xian , Tengfei Hao , Shiwei Zhang , Tianshun Gao , Jie Zhou , Jia Li , Changhua Zhang , Wei Chen , Leli Zeng , Yulong He
Organoids were successfully established from primary tumor and its metastatic lymph nodes of a patient. These organoids faithfully replicated tumor pathology and genetic characteristics. Organoid-based drug screening was conducted, which revealed significant difference in sensitivity to drugs between organoids dervived from primary tumor versus metastatic lymph nodes. The results guided clinical decisions for personalized treatment for the patient. This approach provides an insightful strategy for advancing treatment for gastric cancer.
{"title":"Organoid models of drug resistant gastric adenosquamous carcinoma: Recapitulating tumor features and refining precision treatment","authors":"Kuan Li , Wenchao Li , Shuying Fu , Chen Wang , Kexin Wang , Huan Yang , Yumei Xian , Tengfei Hao , Shiwei Zhang , Tianshun Gao , Jie Zhou , Jia Li , Changhua Zhang , Wei Chen , Leli Zeng , Yulong He","doi":"10.1016/j.drup.2025.101201","DOIUrl":"10.1016/j.drup.2025.101201","url":null,"abstract":"<div><div>Organoids were successfully established from primary tumor and its metastatic lymph nodes of a patient. These organoids faithfully replicated tumor pathology and genetic characteristics. Organoid-based drug screening was conducted, which revealed significant difference in sensitivity to drugs between organoids dervived from primary tumor versus metastatic lymph nodes. The results guided clinical decisions for personalized treatment for the patient. This approach provides an insightful strategy for advancing treatment for gastric cancer.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101201"},"PeriodicalIF":15.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967274","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 : 2025-01-02DOI: 10.1016/j.drup.2024.101199
Yi Xu , Shengwen Calvin Li , Jeffrey Xiao , Qian Liu , Durga Cherukuri , Yan Liu , Saied Mirshahidi , Jane Xu , Xuelian Chen , Dadrastoussi Homa , Julian Olea , Kaijin Wu , Kevin R. Kelly , Fengzhu Sun , Ruihao Huang , Xiaoqi Wang , Qin Wen , Xi Zhang , Cristina M. Ghiuzeli , Esther Chong , Jiang F. Zhong
Chromosomal rearrangements (CR) initiate leukemogenesis in approximately 50 % of acute myeloid leukemia (AML) patients; however, limited targeted therapies exist due to a lack of accurate molecular and genetic biomarkers of refractory mechanisms during treatment. Here, we investigated the pathological landscape of treatment resistance and relapse in 16 CR-AML patients by monitoring cytogenetic, RNAseq, and genome-wide changes among newly diagnosed, refractory, and relapsed AML. First, in FISH-diagnosed KMT2A (MLL gene, 11q23)/AFDN (AF6, 6q27)-rearrangement, RNA-sequencing identified an unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion in both newly diagnosed and relapsed samples, which is previously unknown in KMT2A/AFDN-rearranged AML patients. Second, the unreported CCDC32/CBX3 gene fusion significantly affected the expression of wild-type genes of both CCDC32 (essential for embryonic development) and CBX3 (an oncogene for solid tumors) during the relapse, as demonstrated by Quantitative PCR analyses. Third, we further confirmed the existence of triple biomarkers - KMT2A/AFDN (AF6, 6q27) rearrangement, the unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion and chimeric RNA variants (treatment-resistant leukemic blasts harboring distinct breakpoints) in a 21-year-old male patient of rapid relapsed/refractory AML. Most intriguingly, in this work regarding 16 patients, patients 7 and 20 initially showed the KMT2A/AFDN gene fusion; upon relapse, patient 20 did not show this fusion. On the other hand, patient 7 retained the KMT2A/AFDN fusion at diagnosis and during the relapse, only identified by PCR and Sanger's Sequencing, not by cytogenetics. Interestingly, the chimeric CCDC32/CBX3 gene fusion persisted in the 21-year-old male patient over the diagnostic and relapse phases. Most intriguingly, the overexpression of CCDC32/CBX3 fusion gene in AML patient-specific MV4-11 cells confirms the functional validation, providing experimental evidence of the biological impact of the CCDC32/CBX3 fusion on AML pathogenesis and treatment resistance by promoting cell cycle progression, a mechanism through which AML evolves to become treatment-resistant. All these might exhort differential resistance to treatment. Thus, we found that prognostic and predictive triple biomarkers - KRAS mutated, dual fusions (KMT2A/AFDN, CCDC32/CBX3), and chimeric variants - might evolve with a potential oncogenic role of subclonal evolution for poor clinical outcomes.
{"title":"Exploring treatment-driven subclonal evolution of prognostic triple biomarkers: Dual gene fusions and chimeric RNA variants in novel subtypes of acute myeloid leukemia patients with KMT2A rearrangement","authors":"Yi Xu , Shengwen Calvin Li , Jeffrey Xiao , Qian Liu , Durga Cherukuri , Yan Liu , Saied Mirshahidi , Jane Xu , Xuelian Chen , Dadrastoussi Homa , Julian Olea , Kaijin Wu , Kevin R. Kelly , Fengzhu Sun , Ruihao Huang , Xiaoqi Wang , Qin Wen , Xi Zhang , Cristina M. Ghiuzeli , Esther Chong , Jiang F. Zhong","doi":"10.1016/j.drup.2024.101199","DOIUrl":"10.1016/j.drup.2024.101199","url":null,"abstract":"<div><div>Chromosomal rearrangements (CR) initiate leukemogenesis in approximately 50 % of acute myeloid leukemia (AML) patients; however, limited targeted therapies exist due to a lack of accurate molecular and genetic biomarkers of refractory mechanisms during treatment. Here, we investigated the pathological landscape of treatment resistance and relapse in 16 CR-AML patients by monitoring cytogenetic, RNAseq, and genome-wide changes among newly diagnosed, refractory, and relapsed AML. First, in FISH-diagnosed KMT2A (MLL gene, 11q23)/AFDN (AF6, 6q27)-rearrangement, RNA-sequencing identified an unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion in both newly diagnosed and relapsed samples, which is previously unknown in KMT2A/AFDN-rearranged AML patients. Second, the unreported CCDC32/CBX3 gene fusion significantly affected the expression of wild-type genes of both CCDC32 (essential for embryonic development) and CBX3 (an oncogene for solid tumors) during the relapse, as demonstrated by Quantitative PCR analyses. Third, we further confirmed the existence of triple biomarkers - KMT2A/AFDN (AF6, 6q27) rearrangement, the unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion and chimeric RNA variants (treatment-resistant leukemic blasts harboring distinct breakpoints) in a 21-year-old male patient of rapid relapsed/refractory AML. Most intriguingly, in this work regarding 16 patients, patients 7 and 20 initially showed the KMT2A/AFDN gene fusion; upon relapse, patient 20 did not show this fusion. On the other hand, patient 7 retained the KMT2A/AFDN fusion at diagnosis and during the relapse, only identified by PCR and Sanger's Sequencing, not by cytogenetics. Interestingly, the chimeric CCDC32/CBX3 gene fusion persisted in the 21-year-old male patient over the diagnostic and relapse phases. Most intriguingly, the overexpression of CCDC32/CBX3 fusion gene in AML patient-specific MV4-11 cells confirms the functional validation, providing experimental evidence of the biological impact of the CCDC32/CBX3 fusion on AML pathogenesis and treatment resistance by promoting cell cycle progression, a mechanism through which AML evolves to become treatment-resistant. All these might exhort differential resistance to treatment. Thus, we found that prognostic and predictive triple biomarkers - KRAS mutated, dual fusions (KMT2A/AFDN, CCDC32/CBX3), and chimeric variants - might evolve with a potential oncogenic role of subclonal evolution for poor clinical outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101199"},"PeriodicalIF":15.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990322","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 : 2025-01-02DOI: 10.1016/j.drup.2024.101200
Xingdi Fan , Fangyi Han , Haocheng Wang , Zhilin Shu , Bowen Qiu , Fanan Zeng , Hongzhen Chen , Ziying Wu , Yongwei Lin , Zhien Lan , Zhiwei Ye , Yao Ying , Tiansu Geng , Ziqian Xian , Xing Niu , Junming Wu , Ke Mo , Kehong Zheng , Yaping Ye , Chunhui Cui
Aims
Chemoresistance results in poor outcomes of patients with gastric cancer (GC). This study aims to identify oxaliplatin resistance-related cell subpopulations in the tumor microenvironment (TME) and decipher the involved molecular mechanisms.
Methods
Through single-cell RNA sequencing, a unique ONECUT2+TFPI+ GC cell subset was identified in the oxaliplatin-resistant TME. The functional roles and molecular mechanisms of ONECUT2 in oxaliplatin resistance were investigated in cellular and mouse models. Therapeutic efficacy of small molecule inhibitor of ONECUT2 was also evaluated.
Results
The abundance of ONECUT2+TFPI+ GC cell subset was elevated in oxaliplatin-resistant GC tumors. ONECUT2 was up-regulated and associated with undesirable prognostic outcomes of patients with GC. ONECUT2 facilitated GC cell migration, stemness properties and oxaliplatin resistance. YTHDF2, an m6A “reader”, was down-regulated in GC, and its overexpression facilitated ONECUT2 mRNA degradation through m6A modification. Furthermore, ONECUT2 transcriptionally activated TFPI through binding to its promoter. Small molecule inhibitor CSRM617 targeting ONECUT2 was well tolerated in GC mouse models, and could effectively improve therapeutic efficacy of oxaliplatin against GC.
Conclusions
Our study demonstrates that YTHDF2-mediated m6A modification of ONECUT2 results in stemness and oxaliplatin resistance in GC through transcriptionally activating TFPI, which provides a novel therapeutic target against oxaliplatin-resistant GC.
{"title":"YTHDF2-mediated m6A modification of ONECUT2 promotes stemness and oxaliplatin resistance in gastric cancer through transcriptionally activating TFPI","authors":"Xingdi Fan , Fangyi Han , Haocheng Wang , Zhilin Shu , Bowen Qiu , Fanan Zeng , Hongzhen Chen , Ziying Wu , Yongwei Lin , Zhien Lan , Zhiwei Ye , Yao Ying , Tiansu Geng , Ziqian Xian , Xing Niu , Junming Wu , Ke Mo , Kehong Zheng , Yaping Ye , Chunhui Cui","doi":"10.1016/j.drup.2024.101200","DOIUrl":"10.1016/j.drup.2024.101200","url":null,"abstract":"<div><h3>Aims</h3><div>Chemoresistance results in poor outcomes of patients with gastric cancer (GC). This study aims to identify oxaliplatin resistance-related cell subpopulations in the tumor microenvironment (TME) and decipher the involved molecular mechanisms.</div></div><div><h3>Methods</h3><div>Through single-cell RNA sequencing, a unique <em>ONECUT2</em><sup>+</sup><em>TFPI</em><sup>+</sup> GC cell subset was identified in the oxaliplatin-resistant TME. The functional roles and molecular mechanisms of ONECUT2 in oxaliplatin resistance were investigated in cellular and mouse models. Therapeutic efficacy of small molecule inhibitor of ONECUT2 was also evaluated.</div></div><div><h3>Results</h3><div>The abundance of <em>ONECUT2</em><sup>+</sup><em>TFPI</em><sup>+</sup> GC cell subset was elevated in oxaliplatin-resistant GC tumors. ONECUT2 was up-regulated and associated with undesirable prognostic outcomes of patients with GC. ONECUT2 facilitated GC cell migration, stemness properties and oxaliplatin resistance. YTHDF2, an m<sup>6</sup>A “reader”, was down-regulated in GC, and its overexpression facilitated <em>ONECUT2</em> mRNA degradation through m<sup>6</sup>A modification. Furthermore, ONECUT2 transcriptionally activated <em>TFPI</em> through binding to its promoter. Small molecule inhibitor CSRM617 targeting ONECUT2 was well tolerated in GC mouse models, and could effectively improve therapeutic efficacy of oxaliplatin against GC.</div></div><div><h3>Conclusions</h3><div>Our study demonstrates that YTHDF2-mediated m<sup>6</sup>A modification of ONECUT2 results in stemness and oxaliplatin resistance in GC through transcriptionally activating <em>TFPI</em>, which provides a novel therapeutic target against oxaliplatin-resistant GC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101200"},"PeriodicalIF":15.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990313","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 : 2025-01-01DOI: 10.1016/j.drup.2024.101179
Yifan Chen , Yulong Mi , Song Tan , Yizhen Chen , Shaolin Liu , Shengtao Lin , Changshun Yang , Weifeng Hong , Weihua Li
Background
The serum level of carcinoembryonic antigen (CEA) has prognostic value in patients with gastric cancer (GC) receiving oxaliplatin-based chemotherapy. As the molecular functions of CEA are increasingly uncovered, its role in regulating oxaliplatin resistance in GC attracts attention.
Methods
The survival analysis adopted the KaplanMeier method. Effects of CEA on proliferative capacity were investigated using CCK8, colony formation, and xenograft assays. Oxaliplatin sensitivity was identified through IC50 detection, apoptosis analysis, comet assay, organoid culture model, and xenograft assay. Multi-omics approaches were utilized to explore CEA’s downstream effects. The binding of CEA to KRT1 was confirmed through proteomic analysis and Co-IP, GST pull-down, and immunofluorescence colocalization assays. Furthermore, small molecule inhibitors were identified using virtual screening and surface plasmon resonance.
Results
Starting from clinical data, we confirmed that CEA demonstrated superior ability to predict the prognosis of patients with GC who received oxaliplatin-based chemotherapy, particularly in predicting recurrence-free survival based on serum CEA level. In vitro and in vivo experiments revealed CEAhigh GC cells presented increased proliferative capacity and decreased oxaliplatin sensitivity. The resistance phenotype was transmitted through secreted CEA. Multi-omics analysis revealed that CEA activated the PI3K/AKT pathway by binding to KRT1, leading to oxaliplatin resistance. Finally, the small molecule inhibitor evacetrapib, which competitively inhibits the CEA-KRT1 interaction, was identified and validated in vitro.
Conclusions
In summary, the CEA-KRT1-PI3K/AKT axis regulates oxaliplatin sensitivity in GC cells. Treatment with small molecule inhibitors such as evacetrapib to inhibit this interaction constitutes a novel therapeutic strategy.
{"title":"CEA-induced PI3K/AKT pathway activation through the binding of CEA to KRT1 contributes to oxaliplatin resistance in gastric cancer","authors":"Yifan Chen , Yulong Mi , Song Tan , Yizhen Chen , Shaolin Liu , Shengtao Lin , Changshun Yang , Weifeng Hong , Weihua Li","doi":"10.1016/j.drup.2024.101179","DOIUrl":"10.1016/j.drup.2024.101179","url":null,"abstract":"<div><h3>Background</h3><div>The serum level of carcinoembryonic antigen (CEA) has prognostic value in patients with gastric cancer (GC) receiving oxaliplatin-based chemotherapy. As the molecular functions of CEA are increasingly uncovered, its role in regulating oxaliplatin resistance in GC attracts attention.</div></div><div><h3>Methods</h3><div>The survival analysis adopted the Kaplan<img>Meier method. Effects of CEA on proliferative capacity were investigated using CCK8, colony formation, and xenograft assays. Oxaliplatin sensitivity was identified through IC<sub>50</sub> detection, apoptosis analysis, comet assay, organoid culture model, and xenograft assay. Multi-omics approaches were utilized to explore CEA’s downstream effects. The binding of CEA to KRT1 was confirmed through proteomic analysis and Co-IP, GST pull-down, and immunofluorescence colocalization assays. Furthermore, small molecule inhibitors were identified using virtual screening and surface plasmon resonance.</div></div><div><h3>Results</h3><div>Starting from clinical data, we confirmed that CEA demonstrated superior ability to predict the prognosis of patients with GC who received oxaliplatin-based chemotherapy, particularly in predicting recurrence-free survival based on serum CEA level. In vitro and in vivo experiments revealed CEA<sup>high</sup> GC cells presented increased proliferative capacity and decreased oxaliplatin sensitivity. The resistance phenotype was transmitted through secreted CEA. Multi-omics analysis revealed that CEA activated the PI3K/AKT pathway by binding to KRT1, leading to oxaliplatin resistance. Finally, the small molecule inhibitor evacetrapib, which competitively inhibits the CEA-KRT1 interaction, was identified and validated in vitro.</div></div><div><h3>Conclusions</h3><div>In summary, the CEA-KRT1-PI3K/AKT axis regulates oxaliplatin sensitivity in GC cells. Treatment with small molecule inhibitors such as evacetrapib to inhibit this interaction constitutes a novel therapeutic strategy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101179"},"PeriodicalIF":15.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790068","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 : 2025-01-01DOI: 10.1016/j.drup.2024.101181
Chuan-Jian Shi , Feng-Xiang Pang , Yu-He Lei , Li-Qiang Deng , Fu-Zhen Pan , Zhi-Qing Liang , Tian Xie , Xian-Lin Wu , Yu-Yan Wang , Yan-Fang Xian , Wei-Qiang Zeng , Han-Li Lin , Jin-Fang Zhang
Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) play a crucial role in sorafenib resistance in hepatocellular carcinoma (HCC), and lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a dysregulated lncRNA in sorafenib-resistant HCC cells. However, the underlying regulatory mechanisms of MALAT1 in sorafenib-resistant HCC cells remain unclear. In the present study, we demonstrated that 5-methylcytosine (m5C) methylation catalyzed by NSUN2 and ALYREF contributed to the RNA stability and upregulation of MALAT1. The NSUN2/ALYREF/MALAT1 signaling axis was activated in sorafenib-resistant cells, and the upregulation of MALAT1 inhibited sorafenib-induced ferroptosis to drive sorafenib resistance. Mechanistically, MALAT1 maintained the mRNA stability of SLC7A11 by directly binding to ELAVL1 and stimulating its cytoplasmic translocation. Furthermore, we explored a new synergetic strategy for the treatment of HCC by combining MALAT1 inhibitor MALAT1-IN1 with sorafenib. The results demonstrated that MALAT1-IN1 significantly enhanced sorafenib efficacy for the treatment of HCC both in vitro and in vivo. Collectively, our work brings new insights into the epigenetic mechanisms of sorafenib resistance and offers an alternative therapeutic strategy targeting ferroptosis for sorafenib-resistant HCC patients.
{"title":"5-methylcytosine methylation of MALAT1 promotes resistance to sorafenib in hepatocellular carcinoma through ELAVL1/SLC7A11-mediated ferroptosis","authors":"Chuan-Jian Shi , Feng-Xiang Pang , Yu-He Lei , Li-Qiang Deng , Fu-Zhen Pan , Zhi-Qing Liang , Tian Xie , Xian-Lin Wu , Yu-Yan Wang , Yan-Fang Xian , Wei-Qiang Zeng , Han-Li Lin , Jin-Fang Zhang","doi":"10.1016/j.drup.2024.101181","DOIUrl":"10.1016/j.drup.2024.101181","url":null,"abstract":"<div><div>Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) play a crucial role in sorafenib resistance in hepatocellular carcinoma (HCC), and lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a dysregulated lncRNA in sorafenib-resistant HCC cells. However, the underlying regulatory mechanisms of MALAT1 in sorafenib-resistant HCC cells remain unclear. In the present study, we demonstrated that 5-methylcytosine (m<sup>5</sup>C) methylation catalyzed by NSUN2 and ALYREF contributed to the RNA stability and upregulation of MALAT1. The NSUN2/ALYREF/MALAT1 signaling axis was activated in sorafenib-resistant cells, and the upregulation of MALAT1 inhibited sorafenib-induced ferroptosis to drive sorafenib resistance. Mechanistically, MALAT1 maintained the mRNA stability of SLC7A11 by directly binding to ELAVL1 and stimulating its cytoplasmic translocation. Furthermore, we explored a new synergetic strategy for the treatment of HCC by combining MALAT1 inhibitor MALAT1-IN1 with sorafenib. The results demonstrated that MALAT1-IN1 significantly enhanced sorafenib efficacy for the treatment of HCC both <em>in vitro</em> and <em>in vivo.</em> Collectively, our work brings new insights into the epigenetic mechanisms of sorafenib resistance and offers an alternative therapeutic strategy targeting ferroptosis for sorafenib-resistant HCC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101181"},"PeriodicalIF":15.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808390","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 : 2025-01-01DOI: 10.1016/j.drup.2024.101180
Qian Liu, Hong Shen, Ming Wei, Xi Chen, Li Gu, Wentao Zhu
Morganella morganii has been recognized as an important opportunistic pathogen that is becoming increasingly prevalent worldwide. However, the current global evolutionary dynamics and emergence of ARGs remain obscure. The present study determined the global distribution, genomic classification, phylogeny, and monitor longitudinal resistome changes. During 1900–2024, a total of 1027 non-duplicate Morganella genomes have been reported from 49 countries. The countries with the highest number were China (433), the USA (143), and France (74). Through ANI distance analysis and core genome phylogeny, Morganella was reclassified into six species: M. morganii, M. sibonii, M. chanii, M. laugraudii, M. kristinii, M. psychrotolerans. Further analysis using cgMLST identified 87 distinct genetic clusters and 737 singleton strains, indicating a high level of multi-locus sequence type diversity and local clonal outbreaks. Bayesian evolutionary analysis revealed the most recent common ancestor year and potential global transmission routes. A total of 195 ARGs were carried by Morganella isolates, with each genome containing between 2 and 544 ARGs. The most common ARGs were associated with resistance to the following drug-classes: aminoglycosides, beta-lactam, chloramphenicol, sulfamides, and tetracycline. Twenty-one carbapenemase-encoding genes were identified in 22 countries, with blaNDM-1, blaKPC-2, blaIMP-27, blaOXA-48, blaNDM-5, blaNDM-7, and blaVIM-1 being the most prevalent. Positive correlations were observed between ARGs and mobile genetic elements, like plasmids, ISs, and Tns, indicating frequent mobilization of certain ARGs by different mobile genetic elements (p < 0.05). In conclusion, Morganella isolates that are showing an upward trend in resistance and infection rates warrant a reclassification of their taxonomy and continuous monitoring for resistance.
{"title":"Global phylogeography and antibiotic resistance characteristics of Morganella: An epidemiological, spatial, comparative genomic study","authors":"Qian Liu, Hong Shen, Ming Wei, Xi Chen, Li Gu, Wentao Zhu","doi":"10.1016/j.drup.2024.101180","DOIUrl":"10.1016/j.drup.2024.101180","url":null,"abstract":"<div><div><em>Morganella morganii</em> has been recognized as an important opportunistic pathogen that is becoming increasingly prevalent worldwide. However, the current global evolutionary dynamics and emergence of ARGs remain obscure. The present study determined the global distribution, genomic classification, phylogeny, and monitor longitudinal resistome changes. During 1900–2024, a total of 1027 non-duplicate <em>Morganella</em> genomes have been reported from 49 countries. The countries with the highest number were China (433), the USA (143), and France (74). Through ANI distance analysis and core genome phylogeny, <em>Morganella</em> was reclassified into six species: <em>M. morganii, M. sibonii</em>, <em>M. chanii, M. laugraudii, M. kristinii, M. psychrotolerans</em>. Further analysis using cgMLST identified 87 distinct genetic clusters and 737 singleton strains, indicating a high level of multi-locus sequence type diversity and local clonal outbreaks. Bayesian evolutionary analysis revealed the most recent common ancestor year and potential global transmission routes. A total of 195 ARGs were carried by <em>Morganella</em> isolates, with each genome containing between 2 and 544 ARGs. The most common ARGs were associated with resistance to the following drug-classes: aminoglycosides, beta-lactam, chloramphenicol, sulfamides, and tetracycline. Twenty-one carbapenemase-encoding genes were identified in 22 countries, with <em>bla</em><sub>NDM-1</sub>, <em>bla</em><sub>KPC-2</sub>, <em>bla</em><sub>IMP-27</sub>, <em>bla</em><sub>OXA-48</sub>, <em>bla</em><sub>NDM-5</sub>, <em>bla</em><sub>NDM-7</sub>, and <em>bla</em><sub>VIM-1</sub> being the most prevalent. Positive correlations were observed between ARGs and mobile genetic elements, like plasmids, ISs, and Tns, indicating frequent mobilization of certain ARGs by different mobile genetic elements (<em>p</em> < 0.05). In conclusion, <em>Morganella</em> isolates that are showing an upward trend in resistance and infection rates warrant a reclassification of their taxonomy and continuous monitoring for resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"78 ","pages":"Article 101180"},"PeriodicalIF":15.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808475","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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