Cancer therapy resistance remains a major barrier to successful treatment, often leading to reduced clinical efficacy or cancer relapse. Synthetic lethality (SL) has emerged as a promising strategy to exploit genetic vulnerabilities in cancer cells, allowing for more selective and less toxic therapies. By leveraging the genetic or non-genetic adaptations that cancer cells develop under therapeutic pressure, SL-based therapies provide a more precise and less toxic treatment approach. Additionally, SL-driven drug combinations not only delay development of drug resistance but also enhance therapeutic efficacy, representing a transformative shift in cancer management. A comprehensive understanding of SL mechanisms in the context of drug resistance is essential for advancing effective treatment strategies. This review highlights recent advances in SL research, emphasizing the gene screening techniques in overcoming cancer therapy resistance.
{"title":"The role of synthetic lethality in overcoming cancer therapy resistance: Emerging paradigm and recent advances.","authors":"Qingyi Xiong, Jinmei Jin, Jiayi Lin, Bohan Zhang, Yixin Jiang, Zhe Sun, Lijun Zhang, Ye Wu, Guozhi Zhao, Jiang-Jiang Qin, Xin Luan","doi":"10.1016/j.drup.2025.101290","DOIUrl":"10.1016/j.drup.2025.101290","url":null,"abstract":"<p><p>Cancer therapy resistance remains a major barrier to successful treatment, often leading to reduced clinical efficacy or cancer relapse. Synthetic lethality (SL) has emerged as a promising strategy to exploit genetic vulnerabilities in cancer cells, allowing for more selective and less toxic therapies. By leveraging the genetic or non-genetic adaptations that cancer cells develop under therapeutic pressure, SL-based therapies provide a more precise and less toxic treatment approach. Additionally, SL-driven drug combinations not only delay development of drug resistance but also enhance therapeutic efficacy, representing a transformative shift in cancer management. A comprehensive understanding of SL mechanisms in the context of drug resistance is essential for advancing effective treatment strategies. This review highlights recent advances in SL research, emphasizing the gene screening techniques in overcoming cancer therapy resistance.</p>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"101290"},"PeriodicalIF":21.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812629","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 : 2025-10-29DOI: 10.1016/j.drup.2025.101320
Jian Xu , Nhan Dai Thien Tram , Peiyan Yu, Dhanya Mahalakshmi Murali, Wei Meng Chen, Samantha Jinglin Yang , Pui Lai Rachel Ee
Aims
In the presence of antibiotics, motile bacteria can navigate chemical gradients for adaptation and survival. Antimicrobial peptides (AMPs) have been widely explored as adjuvant to improve the activity potency of antibiotics, but mainly through the disruption of bacterial membranes. In this work, we investigated the impact of nanonet trapping using fibrillating peptides, a mechanistically unique sub-group of AMPs, on motility recovery of bacteria and their capacity to develop antibiotic resistance.
Methods
The ability of fibrillating AMPs to potentiate activity and delay resistance of antibiotics from diverse classes was evaluated against clinical isolates of Gram-negative pathogens. Using soft agar assay and live-tracking microscopy, shifts in the motility of the bacteria population subjected to different treatments were evaluated. To further elucidate the mechanism of action, the expression of major flagella-encoding genes was quantified and hypomotile bacteria strains were studied.
Results
At sub-inhibitory concentrations, fibrillating peptides not only displayed synergistic interactions, but also significantly delayed the emergence of resistance to antibiotics such as rifampicin for at least 18 days. The peptide-antibiotic synergy profiles were lost after prolonged treatment with antibiotic monotherapy but preserved when co-administered with fibrillating peptides throughout the serial passage. The nanonet-forming peptides were shown to serve as a motility filter where the bacteria population gradually shifted towards homogeneous hypomotility associated with inferior survivability.
Conclusions
This work showcases the potential of AMPs as low-concentration adjuvants for extending the clinical lifespan of current antibiotics and highlights bacterial motility as an underexplored target for antibiotic development.
{"title":"Peptide nanonet trapping suppresses bacterial motility and delays antibiotic resistance emergence","authors":"Jian Xu , Nhan Dai Thien Tram , Peiyan Yu, Dhanya Mahalakshmi Murali, Wei Meng Chen, Samantha Jinglin Yang , Pui Lai Rachel Ee","doi":"10.1016/j.drup.2025.101320","DOIUrl":"10.1016/j.drup.2025.101320","url":null,"abstract":"<div><h3>Aims</h3><div>In the presence of antibiotics, motile bacteria can navigate chemical gradients for adaptation and survival. Antimicrobial peptides (AMPs) have been widely explored as adjuvant to improve the activity potency of antibiotics, but mainly through the disruption of bacterial membranes. In this work, we investigated the impact of nanonet trapping using fibrillating peptides, a mechanistically unique sub-group of AMPs, on motility recovery of bacteria and their capacity to develop antibiotic resistance.</div></div><div><h3>Methods</h3><div>The ability of fibrillating AMPs to potentiate activity and delay resistance of antibiotics from diverse classes was evaluated against clinical isolates of Gram-negative pathogens. Using soft agar assay and live-tracking microscopy, shifts in the motility of the bacteria population subjected to different treatments were evaluated. To further elucidate the mechanism of action, the expression of major flagella-encoding genes was quantified and hypomotile bacteria strains were studied.</div></div><div><h3>Results</h3><div>At sub-inhibitory concentrations, fibrillating peptides not only displayed synergistic interactions, but also significantly delayed the emergence of resistance to antibiotics such as rifampicin for at least 18 days. The peptide-antibiotic synergy profiles were lost after prolonged treatment with antibiotic monotherapy but preserved when co-administered with fibrillating peptides throughout the serial passage. The nanonet-forming peptides were shown to serve as a motility filter where the bacteria population gradually shifted towards homogeneous hypomotility associated with inferior survivability.</div></div><div><h3>Conclusions</h3><div>This work showcases the potential of AMPs as low-concentration adjuvants for extending the clinical lifespan of current antibiotics and highlights bacterial motility as an underexplored target for antibiotic development.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101320"},"PeriodicalIF":21.7,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382791","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 : 2025-10-28DOI: 10.1016/j.drup.2025.101319
Shen-nan Shi , Qiuyang Xu , Zhiqi Liao , Wenjian Gong , Yilin Cui , Jiahao Liu , Xiaofei Jiao , Yijie Wu , Mengshi Luo , Yuewen Zhang , Linghui Wang , Yuanjia Wen , Wen Pan , Xuejiao Zhao , Marilyne Labrie , Zhiyong Ding , Gordon B. Mills , Ding Ma , Guang-Nian Zhao , Qinglei Gao , Yong Fang
ZBP1, a classic pattern recognition receptor (PRR), has been implicated in regulating programmed cell death and the innate immune response. However, the role of ZBP1 in the nucleus remains largely undefined. Here, we found that nuclear ZBP1 localizes to the site of DNA double-stranded breaks (DSBs) following DNA damage and impairs homologous recombination (HR) repair through its interaction with MRE11. ZBP1 interacts with MRE11 through RHIM A and B domains and inhibits the enzymatic activity of MRE11, ultimately leading to the suppression of HR and DNA damage repair (DDR). These processes are initiated via ATM-mediated ZBP1 phosphorylation at S106. Consistent with these findings, in vitro and in vivo models both exhibit increased sensitivity to PARP inhibitor treatment following ZBP1 overexpression. Furthermore, in our neoadjuvant niraparib monotherapy study (NCT05407841) higher ZBP1 expression correlates with better response to PARP inhibition and prolonged PFS in high-grade serous ovarian cancer (HGSOC). This study describes a novel function of ZBP1 for regulating HR, which confers synthetic lethality to PARP inhibition in ovarian cancer. ZBP1 thus serves as a potential therapy target and biomarker of response to PARP inhibitors and potentially other therapeutic agents such as platin analogs that are synthetically lethal with defective HR.
{"title":"ZBP1 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in ovarian cancer","authors":"Shen-nan Shi , Qiuyang Xu , Zhiqi Liao , Wenjian Gong , Yilin Cui , Jiahao Liu , Xiaofei Jiao , Yijie Wu , Mengshi Luo , Yuewen Zhang , Linghui Wang , Yuanjia Wen , Wen Pan , Xuejiao Zhao , Marilyne Labrie , Zhiyong Ding , Gordon B. Mills , Ding Ma , Guang-Nian Zhao , Qinglei Gao , Yong Fang","doi":"10.1016/j.drup.2025.101319","DOIUrl":"10.1016/j.drup.2025.101319","url":null,"abstract":"<div><div>ZBP1, a classic pattern recognition receptor (PRR), has been implicated in regulating programmed cell death and the innate immune response. However, the role of ZBP1 in the nucleus remains largely undefined. Here, we found that nuclear ZBP1 localizes to the site of DNA double-stranded breaks (DSBs) following DNA damage and impairs homologous recombination (HR) repair through its interaction with MRE11. ZBP1 interacts with MRE11 through RHIM A and B domains and inhibits the enzymatic activity of MRE11, ultimately leading to the suppression of HR and DNA damage repair (DDR). These processes are initiated via ATM-mediated ZBP1 phosphorylation at S106. Consistent with these findings, <em>in vitro</em> and <em>in vivo</em> models both exhibit increased sensitivity to PARP inhibitor treatment following ZBP1 overexpression. Furthermore, in our neoadjuvant niraparib monotherapy study (NCT05407841) higher ZBP1 expression correlates with better response to PARP inhibition and prolonged PFS in high-grade serous ovarian cancer (HGSOC). This study describes a novel function of ZBP1 for regulating HR, which confers synthetic lethality to PARP inhibition in ovarian cancer. ZBP1 thus serves as a potential therapy target and biomarker of response to PARP inhibitors and potentially other therapeutic agents such as platin analogs that are synthetically lethal with defective HR.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101319"},"PeriodicalIF":21.7,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382804","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 : 2025-10-17DOI: 10.1016/j.drup.2025.101316
Lingmin Zhang , Linlong He , Yinshan Lin , Juyan Wei , Shiqi Tang , Xueping Lei , Xufeng Lin , Dazhi Zhou , Liwu Fu , Yuehua Li , Juyun He , Lu Liang , Xi-Yong Yu
Current pharmacotherapy on the fatal lung cancer is often limited by the development of drug resistance, which significantly contributes to treatment failure. The drug resistance in cancer is associated with tumor microenvironment (TME), particularly with cancer-associated fibroblasts (CAFs). However, the present approaches show little progress in the eliminating lung cancer cells and reversing the TME synergistically. The emergence of nanomedicine offers promising strategies to overcome this challenge. In this study, we developed a proteolysis-targeting chimeras (PROTAC)-based nanodrug, designed to eliminate both lung cancer cells and CAFs, thereby amplifying the therapeutic effects. This nanodrug was constructed by loading dBET6 with US Food and Drug Administration (FDA) approved polymer Poly(lactic-co-glycolic acid) (PLGA), and further camouflaged with the hybrid membranes derived from platelet and lung cancer cells (PLMPD). PLMPD demonstrated excellent dual-targeting capabilities to both lung cancer cells and CAFs, leading to significant apoptosis in both cell types in vitro. We also found that PLMPD could inhibited the growth of Osimertinib-resistant cells. In vivo studies revealed that PLMPD enhanced tumor targeting, effectively inhibited tumor growth, and reversed the tumor-promoting TME in the lung cancer xenograft models. These findings underscore the potential of PLMPD as a promising PROTAC-based nanodrug for lung cancer therapy, offering a new avenue for overcoming drug resistance and improving treatment outcomes.
{"title":"The novel strategy to overcome the drug-resistant lung cancer: Dual targeting delivery of PROTAC to inhibit cancer-associated fibroblasts and lung cancer cells","authors":"Lingmin Zhang , Linlong He , Yinshan Lin , Juyan Wei , Shiqi Tang , Xueping Lei , Xufeng Lin , Dazhi Zhou , Liwu Fu , Yuehua Li , Juyun He , Lu Liang , Xi-Yong Yu","doi":"10.1016/j.drup.2025.101316","DOIUrl":"10.1016/j.drup.2025.101316","url":null,"abstract":"<div><div>Current pharmacotherapy on the fatal lung cancer is often limited by the development of drug resistance, which significantly contributes to treatment failure. The drug resistance in cancer is associated with tumor microenvironment (TME), particularly with cancer-associated fibroblasts (CAFs). However, the present approaches show little progress in the eliminating lung cancer cells and reversing the TME synergistically. The emergence of nanomedicine offers promising strategies to overcome this challenge. In this study, we developed a proteolysis-targeting chimeras (PROTAC)-based nanodrug, designed to eliminate both lung cancer cells and CAFs, thereby amplifying the therapeutic effects. This nanodrug was constructed by loading dBET6 with US Food and Drug Administration (FDA) approved polymer Poly(lactic-co-glycolic acid) (PLGA), and further camouflaged with the hybrid membranes derived from platelet and lung cancer cells (PLMPD). PLMPD demonstrated excellent dual-targeting capabilities to both lung cancer cells and CAFs, leading to significant apoptosis in both cell types in vitro. We also found that PLMPD could inhibited the growth of Osimertinib-resistant cells. In vivo studies revealed that PLMPD enhanced tumor targeting, effectively inhibited tumor growth, and reversed the tumor-promoting TME in the lung cancer xenograft models. These findings underscore the potential of PLMPD as a promising PROTAC-based nanodrug for lung cancer therapy, offering a new avenue for overcoming drug resistance and improving treatment outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101316"},"PeriodicalIF":21.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363515","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 : 2025-10-13DOI: 10.1016/j.drup.2025.101315
Hongbo Zhang , Yue Sun , Rui Liu , Hayam Hamdy , Zhi Shi , Dewei Jiang , Jianwei Sun
Breast cancer stem cells (BCSCs) are recognized as a critical subpopulation involved in cancer recurrence and metastasis, as they are capable of self-renewal and differentiate into various cell types. BCSCs play significant roles in tumor progression, being regulated by key signaling pathways such as Notch, PI3K/AKT/mTOR, and Hedgehog, and their interactions with the tumor microenvironment, which affect tumor growth and resistance to therapeutics. This review focuses on the surface markers of BCSCs, their roles in recurrence and metastasis, and the key signaling pathways. It also discusses the recent progress in understanding how BCSCs contribute to drug resistance and explores potential therapeutic strategies targeting these cells and their microenvironment to improve clinical outcomes and prevent relapse.
{"title":"The role of tumor microenvironment and signaling pathways in regulating breast cancer stem cells: Implications for therapy resistance and tumor recurrence","authors":"Hongbo Zhang , Yue Sun , Rui Liu , Hayam Hamdy , Zhi Shi , Dewei Jiang , Jianwei Sun","doi":"10.1016/j.drup.2025.101315","DOIUrl":"10.1016/j.drup.2025.101315","url":null,"abstract":"<div><div>Breast cancer stem cells (BCSCs) are recognized as a critical subpopulation involved in cancer recurrence and metastasis, as they are capable of self-renewal and differentiate into various cell types. BCSCs play significant roles in tumor progression, being regulated by key signaling pathways such as Notch, PI3K/AKT/mTOR, and Hedgehog, and their interactions with the tumor microenvironment, which affect tumor growth and resistance to therapeutics. This review focuses on the surface markers of BCSCs, their roles in recurrence and metastasis, and the key signaling pathways. It also discusses the recent progress in understanding how BCSCs contribute to drug resistance and explores potential therapeutic strategies targeting these cells and their microenvironment to improve clinical outcomes and prevent relapse.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101315"},"PeriodicalIF":21.7,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314883","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 : 2025-10-09DOI: 10.1016/j.drup.2025.101314
Chunxia Jiang, Dan Wang, Liujun Xu
{"title":"A covalent gambit: An irreversible inhibitor to checkmate drug resistance in tuberculosis","authors":"Chunxia Jiang, Dan Wang, Liujun Xu","doi":"10.1016/j.drup.2025.101314","DOIUrl":"https://doi.org/10.1016/j.drup.2025.101314","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"20 1","pages":"101314"},"PeriodicalIF":24.3,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261683","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 : 2025-10-04DOI: 10.1016/j.drup.2025.101312
Maryam Safari , Luigi Scotto , Agnes Basseville , Thomas Litman , Haoran Xue , Lubov Petrukhin , Ping Zhou , Helen E. Remotti , Amy Ku , Diana V. Morales , Christopher Damoci , Mingzhao Zhu , Ravikanth Maddipati , Kenneth G. Hull , Robert W. Robey , Kenneth P. Olive , Tito Fojo , Daniel Romo , Susan E. Bates
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Emerging evidence suggests that epigenetic therapies have the potential to target key mechanisms driving PDAC progression and therapy resistance. Previous efforts to target KRAS-driven metabolic vulnerabilities, including dependence on enhanced fatty acid synthesis, have highlighted the potential for histone deacetylase (HDAC) inhibitors to deplete acetyl-CoA and induce DNA damage through histone acetylation, while resistance emerges at least in part due to the reversible nature of HDAC inhibitor-induced acetylation. In this work, we discovered that the combination of class I histone deacetylase (HDAC) inhibitors, such as romidepsin, with a novel RNA helicase eIF4A inhibitor, des-methyl pateamine A (DMPatA), induces robust and persistent hyperacetylation, significantly exceeding the levels and duration observed with HDAC inhibitor monotherapy. This combination synergistically reduces the viability of PDAC cells, even at low, nontoxic doses for both drugs. This unexpected synergistic effect triggers a cascade of cellular responses, including hypertranscription, metabolic stress, and augmented DNA damage. Sustained hyperacetylation represents a novel mechanism exploiting PDAC-specific vulnerabilities, simultaneously amplifying DNA damage and depleting acetyl-CoA levels critical for their aberrant proliferation. In vivo, the combination effectively suppresses tumor growth, showing no toxicity to normal tissues but sustained hyperacetylation in tumor tissue. The combination does not appear to induce known resistance mechanisms such as drug efflux; elevated MYC expression, rather than inducing resistance, sensitizes PDAC cells to treatment. These studies support translation of this synergistic combination to the clinic.
{"title":"Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic ductal adenocarcinoma","authors":"Maryam Safari , Luigi Scotto , Agnes Basseville , Thomas Litman , Haoran Xue , Lubov Petrukhin , Ping Zhou , Helen E. Remotti , Amy Ku , Diana V. Morales , Christopher Damoci , Mingzhao Zhu , Ravikanth Maddipati , Kenneth G. Hull , Robert W. Robey , Kenneth P. Olive , Tito Fojo , Daniel Romo , Susan E. Bates","doi":"10.1016/j.drup.2025.101312","DOIUrl":"10.1016/j.drup.2025.101312","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Emerging evidence suggests that epigenetic therapies have the potential to target key mechanisms driving PDAC progression and therapy resistance. Previous efforts to target KRAS-driven metabolic vulnerabilities, including dependence on enhanced fatty acid synthesis, have highlighted the potential for histone deacetylase (HDAC) inhibitors to deplete acetyl-CoA and induce DNA damage through histone acetylation, while resistance emerges at least in part due to the reversible nature of HDAC inhibitor-induced acetylation. In this work, we discovered that the combination of class I histone deacetylase (HDAC) inhibitors, such as romidepsin, with a novel RNA helicase eIF4A inhibitor, des-methyl pateamine A (DMPatA), induces robust and persistent hyperacetylation, significantly exceeding the levels and duration observed with HDAC inhibitor monotherapy. This combination synergistically reduces the viability of PDAC cells, even at low, nontoxic doses for both drugs. This unexpected synergistic effect triggers a cascade of cellular responses, including hypertranscription, metabolic stress, and augmented DNA damage. <em>Sustained hyperacetylation</em> represents a novel mechanism exploiting PDAC-specific vulnerabilities, simultaneously amplifying DNA damage and depleting acetyl-CoA levels critical for their aberrant proliferation. <em>In vivo</em>, the combination effectively suppresses tumor growth, showing no toxicity to normal tissues but sustained hyperacetylation in tumor tissue. The combination does not appear to induce known resistance mechanisms such as drug efflux; elevated MYC expression, rather than inducing resistance, sensitizes PDAC cells to treatment. These studies support translation of this synergistic combination to the clinic.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101312"},"PeriodicalIF":21.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314190","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 : 2025-09-29DOI: 10.1016/j.drup.2025.101313
Yu-Ze Wang , Ning Gao , Zhanwen Lin , Si-Heng Wang , Shichang Ai , Zhanqi Wei , Shuishen Zhang , Junchao Cai , Weixiong Yang , Si-Cong Ma , Chao Cheng
<div><h3>Aims</h3><div>Prognostic and predictive biomarkers are two common biomarker types in clinics, with the former indicating the natural course of cancer regardless of treatment, and the latter determining the response to a specific regimen. Understanding the predictive versus prognostic effect of biomarkers is essential to understand treatment-specific response from the inherent prognosis of cancer. Herein, we aimed to uncover the predictive metabolic signatures specific to immunotherapy resistance by distinguishing the predictive versus prognostic effect of transcriptional programs in advanced non-small cell lung cancer (NSCLC) treated with immunotherapy.</div></div><div><h3>Methods</h3><div>Clinical and transcriptomic data were collected from two randomized controlled trials, OAK (n = 699, discovery cohort) and POPLAR (n = 192, validation cohort) comparing immunotherapy with chemotherapy. Metabolic transcriptional signature scores were calculated through gene set variation analysis. Cox regression and interaction test were conducted to differentiate the predictive versus prognostic effect. Additionally, lung tumor-bearing murine models were established using <em>Slc22a5</em>-overexpressing (OE) and control Lewis Lung Carcinoma (LLC) cells, and treated with immunotherapy or chemotherapy. The translational potential of an SLC22A5 (Solute Carrier Family 22 Member 5) inhibitor in combination with immunotherapy was assessed in preclinical setting. The tumor microenvironment was analyzed by flow cytometry, immunofluorescence, and Enzyme-Linked Immunosorbent Assay (ELISA) to validate the mechanistic findings.</div></div><div><h3>Results</h3><div>Metabolic transcriptional programs were divided into four categories based on different predictive effects specific to immunotherapy or chemotherapy, among which carnitine metabolism stood out as the most prominent metabolic process contributing to the resistance to immunotherapy. Specifically, SLC22A5 as the only high-affinity carnitine transporter was remarkably upregulated in immunotherapy-resistant patients. The predictive effect of SLC22A5-centric carnitine metabolism for resistance to immunotherapy rather than chemotherapy was independently validated in an external randomized trial. Critically, preclinical models revealed that <em>Slc22a5</em> overexpression drove resistance to immunotherapy but not chemotherapy, by fostering an immunosuppressive microenvironment characterized by M2 macrophage accumulation and CD8 + T cell exclusion. Furthermore, pharmacological inhibition of SLC22A5 by meldonium reshaped the tumor microenvironment toward a more inflamed state and re-sensitized resistant tumors to immunotherapy.</div></div><div><h3>Conclusions</h3><div>Our study elucidates the predictive versus prognostic effect of metabolic pathways in advanced NSCLC under immunotherapy. Tumor-intrinsic carnitine metabolism may predict and drive immunotherapy resistance, and targeting SLC22A5-mediated carnitine me
{"title":"Dissection of immunotherapeutic predictive versus prognostic transcriptional programs identifies SLC22A5-centric carnitine metabolism-driven resistance to anti-PD-(L)1 treatment in non-small cell lung cancer","authors":"Yu-Ze Wang , Ning Gao , Zhanwen Lin , Si-Heng Wang , Shichang Ai , Zhanqi Wei , Shuishen Zhang , Junchao Cai , Weixiong Yang , Si-Cong Ma , Chao Cheng","doi":"10.1016/j.drup.2025.101313","DOIUrl":"10.1016/j.drup.2025.101313","url":null,"abstract":"<div><h3>Aims</h3><div>Prognostic and predictive biomarkers are two common biomarker types in clinics, with the former indicating the natural course of cancer regardless of treatment, and the latter determining the response to a specific regimen. Understanding the predictive versus prognostic effect of biomarkers is essential to understand treatment-specific response from the inherent prognosis of cancer. Herein, we aimed to uncover the predictive metabolic signatures specific to immunotherapy resistance by distinguishing the predictive versus prognostic effect of transcriptional programs in advanced non-small cell lung cancer (NSCLC) treated with immunotherapy.</div></div><div><h3>Methods</h3><div>Clinical and transcriptomic data were collected from two randomized controlled trials, OAK (n = 699, discovery cohort) and POPLAR (n = 192, validation cohort) comparing immunotherapy with chemotherapy. Metabolic transcriptional signature scores were calculated through gene set variation analysis. Cox regression and interaction test were conducted to differentiate the predictive versus prognostic effect. Additionally, lung tumor-bearing murine models were established using <em>Slc22a5</em>-overexpressing (OE) and control Lewis Lung Carcinoma (LLC) cells, and treated with immunotherapy or chemotherapy. The translational potential of an SLC22A5 (Solute Carrier Family 22 Member 5) inhibitor in combination with immunotherapy was assessed in preclinical setting. The tumor microenvironment was analyzed by flow cytometry, immunofluorescence, and Enzyme-Linked Immunosorbent Assay (ELISA) to validate the mechanistic findings.</div></div><div><h3>Results</h3><div>Metabolic transcriptional programs were divided into four categories based on different predictive effects specific to immunotherapy or chemotherapy, among which carnitine metabolism stood out as the most prominent metabolic process contributing to the resistance to immunotherapy. Specifically, SLC22A5 as the only high-affinity carnitine transporter was remarkably upregulated in immunotherapy-resistant patients. The predictive effect of SLC22A5-centric carnitine metabolism for resistance to immunotherapy rather than chemotherapy was independently validated in an external randomized trial. Critically, preclinical models revealed that <em>Slc22a5</em> overexpression drove resistance to immunotherapy but not chemotherapy, by fostering an immunosuppressive microenvironment characterized by M2 macrophage accumulation and CD8 + T cell exclusion. Furthermore, pharmacological inhibition of SLC22A5 by meldonium reshaped the tumor microenvironment toward a more inflamed state and re-sensitized resistant tumors to immunotherapy.</div></div><div><h3>Conclusions</h3><div>Our study elucidates the predictive versus prognostic effect of metabolic pathways in advanced NSCLC under immunotherapy. Tumor-intrinsic carnitine metabolism may predict and drive immunotherapy resistance, and targeting SLC22A5-mediated carnitine me","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101313"},"PeriodicalIF":21.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221841","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 : 2025-09-18DOI: 10.1016/j.drup.2025.101311
Ru Jia , Chuan-xing Xiao , Yong-hai Zhang , Li-yang Hu , Y. Jun-jun , Rui Zuo , Yu-fei Hu , Yu-hao Xie , Xue-lei Ma , Qi Li , Kai-jian Hou
Drug resistance, particularly those of anticancer drugs and antibiotics, poses a significant challenge in the treatment of diseases, severely compromising therapeutic efficacy and patient survival rates. In recent years, an increasing number of studies have highlighted the dual role of microbiota in either promoting or mitigating drug resistance. The microbiome exists in symbiosis with the host, playing a crucial role in maintaining physiological functions and regulating immune responses. However, dysbiosis within the microbial community may induce or exacerbate drug resistance. While antibiotic-mediated depletion of gut microbiota has been proposed as a strategy to combat resistance, it may paradoxically lead to increased resistance or even worsen treatment outcomes. In this review, we focus on anticancer and antimicrobial agents as representative examples to elucidate the association of microbiome and drug resistance. We provide a detailed discussion on the mechanisms by which microbial dysbiosis contributes to development of drug resistance. Additionally, we systematically summarize the latest advancements in microbiota-targeted therapeutic strategies aimed at overcoming resistance, including fecal microbiota transplantation, probiotics and prebiotics, and bacterial engineering approaches. Finally, we discuss the potential clinical applications of microbiota-modulating strategies for overcoming drug resistance and examine the current challenges and future research directions in this field.
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