Pub Date : 2025-08-29DOI: 10.1016/j.drup.2025.101296
Sifen Wang , Chao Zhang , Sha Zhou , Shiliang Liu , Qiaoqiao Li , Xingyuan Cheng , Ruixi Wang , Baoqing Chen , Yue Li , Mian Xi
Resistance to chemoradiotherapy is a crucial factor limiting the efficacy of therapy and prognosis of esophageal cancer. It is necessary to elucidate the key genes and regulatory mechanisms responsible for therapeutic resistance in esophageal squamous cell carcinoma (ESCC). In this study, we found a relationship between ferroptosis and therapeutic sensitivity in ESCC and identified the ring finger protein 217 (RNF217) as a new regulator of ferroptosis associated with resistance to chemoradiotherapy in ESCC. Mechanistically, RNF217 interacts with kelch like ECH associated protein 1 (KEAP1) and promotes its ubiquitination and degradation, resulting in nuclear factor erythroid 2-related factor 2 (NRF2) evading KEAP1-mediated degradation and, consequently, enhanced NRF2 signaling and led to ferroptosis resistance. Furthermore, NRF2 facilitated the transcription of RNF217 by binding to antioxidant response elements in the RNF217 promoter upon irradiation. Overall, our findings indicate that the RNF217-KEAP1-NRF2 feedback loop is a previously unrecognized mechanism regulating resistance to chemoradiotherapy in ESCC and could be a target to overcome therapeutic resistance in ESCC.
{"title":"RNF217-KEAP1-NRF2 feedback loop confers therapeutic resistance by inhibiting ferroptosis in esophageal squamous cell carcinoma","authors":"Sifen Wang , Chao Zhang , Sha Zhou , Shiliang Liu , Qiaoqiao Li , Xingyuan Cheng , Ruixi Wang , Baoqing Chen , Yue Li , Mian Xi","doi":"10.1016/j.drup.2025.101296","DOIUrl":"10.1016/j.drup.2025.101296","url":null,"abstract":"<div><div>Resistance to chemoradiotherapy is a crucial factor limiting the efficacy of therapy and prognosis of esophageal cancer. It is necessary to elucidate the key genes and regulatory mechanisms responsible for therapeutic resistance in esophageal squamous cell carcinoma (ESCC). In this study, we found a relationship between ferroptosis and therapeutic sensitivity in ESCC and identified the ring finger protein 217 (RNF217) as a new regulator of ferroptosis associated with resistance to chemoradiotherapy in ESCC. Mechanistically, RNF217 interacts with kelch like ECH associated protein 1 (KEAP1) and promotes its ubiquitination and degradation, resulting in nuclear factor erythroid 2-related factor 2 (NRF2) evading KEAP1-mediated degradation and, consequently, enhanced NRF2 signaling and led to ferroptosis resistance. Furthermore, NRF2 facilitated the transcription of RNF217 by binding to antioxidant response elements in the RNF217 promoter upon irradiation. Overall, our findings indicate that the RNF217-KEAP1-NRF2 feedback loop is a previously unrecognized mechanism regulating resistance to chemoradiotherapy in ESCC and could be a target to overcome therapeutic resistance in ESCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101296"},"PeriodicalIF":21.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988606","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 : 2025-08-20DOI: 10.1016/j.drup.2025.101294
Ling Li , Yangyang Feng , Jingbo Zhou , Fangyuan Shao , Yuzhong Peng , Sitian Zang , Josh Haipeng Lei , Heng Sun , Dongyang Tang , Shiqi Lin , Jinghong Chen , Hanghang Li , Xiangpeng Chu , Yunfeng Qiao , Xinyu Guo , Kakun Wu , Xiaoling Xu , Chu-Xia Deng
Multidrug resistance (MDR) is associated with increased proteasome activity, which facilitates the clearance of damaged proteins and reduced mitochondrial activity, which contributes to quiescence. However, the mechanistic link between protein damage, mitochondrial dysfunction, and proteasome activity remains elusive. Here, we demonstrate that chemical drugs bind to newly synthesized mitochondrial proteins, which are largely unfolded and are coimported into the mitochondrion before appearing in the lysosome and/or nucleus. This triggers a mitochondrion-lysosome–mediated chain reaction, including the integrity stress response (ISR) and the mitochondrial unfolded protein response (UPRmt), followed by increased lysosome biogenesis and PINK1–Parkin independent but ROS–BNIP3–mediated mitophagy. We further observed that proteasomes are the main controller of the mitochondrion-lysosome reaction by monitoring proteostasis, suppressing mitochondrial protein import and promoting mitophagy under both normal and drug-treated conditions. The combination of chemical drugs and the proteasome inhibitor bortezomib (BTZ) triggered excessive mitochondrial import of damaged proteins, overwhelming mitochondrial capacity, causing mitochondrial membrane damage, profound mitochondrial ROS production, lysosome membrane permeabilization, impaired mitophagy, and proteostasis stress-induced cell death.
{"title":"Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy","authors":"Ling Li , Yangyang Feng , Jingbo Zhou , Fangyuan Shao , Yuzhong Peng , Sitian Zang , Josh Haipeng Lei , Heng Sun , Dongyang Tang , Shiqi Lin , Jinghong Chen , Hanghang Li , Xiangpeng Chu , Yunfeng Qiao , Xinyu Guo , Kakun Wu , Xiaoling Xu , Chu-Xia Deng","doi":"10.1016/j.drup.2025.101294","DOIUrl":"10.1016/j.drup.2025.101294","url":null,"abstract":"<div><div>Multidrug resistance (MDR) is associated with increased proteasome activity, which facilitates the clearance of damaged proteins and reduced mitochondrial activity, which contributes to quiescence. However, the mechanistic link between protein damage, mitochondrial dysfunction, and proteasome activity remains elusive. Here, we demonstrate that chemical drugs bind to newly synthesized mitochondrial proteins, which are largely unfolded and are coimported into the mitochondrion before appearing in the lysosome and/or nucleus. This triggers a mitochondrion-lysosome–mediated chain reaction, including the integrity stress response (ISR) and the mitochondrial unfolded protein response (UPR<sup>mt</sup>), followed by increased lysosome biogenesis and PINK1–Parkin independent but ROS–BNIP3–mediated mitophagy. We further observed that proteasomes are the main controller of the mitochondrion-lysosome reaction by monitoring proteostasis, suppressing mitochondrial protein import and promoting mitophagy under both normal and drug-treated conditions. The combination of chemical drugs and the proteasome inhibitor bortezomib (BTZ) triggered excessive mitochondrial import of damaged proteins, overwhelming mitochondrial capacity, causing mitochondrial membrane damage, profound mitochondrial ROS production, lysosome membrane permeabilization, impaired mitophagy, and proteostasis stress-induced cell death.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101294"},"PeriodicalIF":21.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898421","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 : 2025-08-18DOI: 10.1016/j.drup.2025.101293
Xiaofei Fan , Jiahao Liu , Shudong Xie , Hongpei Tan , Ze Mi , Pengpeng Zhang , Xiaoqian Ma , Qi Liang , Min Yang , Yingzi Ming , Pengfei Rong
Radiotherapy efficacy in cancer treatment is frequently compromised by tumor radioresistance, limited immune activation, and off-target toxicity. To address these challenges, we developed a multifunctional nanosystem (FPPF@HC), combining FePt-PEG-FA nanoparticles encapsulated in an HSA-CaP hybrid shell. This platform prolongs systemic circulation, effectively targets tumors via the enhanced permeability and retention effect, and facilitates active folate receptor-mediated uptake. In the acidic tumor microenvironment, the nanoparticles release FePt cores, triggering ferroptosis through Fe²⁺-mediated Fenton reactions, oxidative stress, lipid peroxidation, and subsequent tumor cell death. Concurrently, ferroptosis-induced immunogenic cell death enhances dendritic cell maturation and CD8⁺ effector T cell infiltration, remodeling the tumor immune microenvironment. In vitro and in vivo studies demonstrated significantly improved tumor suppression, radiosensitivity, and immune activation compared with radiotherapy alone. Comprehensive biosafety evaluations indicated minimal systemic toxicity. This nanosystem offers a promising strategy for overcoming radioresistance and improving clinical outcomes in cancer therapy.
{"title":"HSA-templated synergistic platform boosts radiotherapy via enhanced radiosensitization and ferroptosis induction","authors":"Xiaofei Fan , Jiahao Liu , Shudong Xie , Hongpei Tan , Ze Mi , Pengpeng Zhang , Xiaoqian Ma , Qi Liang , Min Yang , Yingzi Ming , Pengfei Rong","doi":"10.1016/j.drup.2025.101293","DOIUrl":"10.1016/j.drup.2025.101293","url":null,"abstract":"<div><div>Radiotherapy efficacy in cancer treatment is frequently compromised by tumor radioresistance, limited immune activation, and off-target toxicity. To address these challenges, we developed a multifunctional nanosystem (FPPF@HC), combining FePt-PEG-FA nanoparticles encapsulated in an HSA-CaP hybrid shell. This platform prolongs systemic circulation, effectively targets tumors via the enhanced permeability and retention effect, and facilitates active folate receptor-mediated uptake. In the acidic tumor microenvironment, the nanoparticles release FePt cores, triggering ferroptosis through Fe²⁺-mediated Fenton reactions, oxidative stress, lipid peroxidation, and subsequent tumor cell death. Concurrently, ferroptosis-induced immunogenic cell death enhances dendritic cell maturation and CD8⁺ effector T cell infiltration, remodeling the tumor immune microenvironment. In vitro and in vivo studies demonstrated significantly improved tumor suppression, radiosensitivity, and immune activation compared with radiotherapy alone. Comprehensive biosafety evaluations indicated minimal systemic toxicity. This nanosystem offers a promising strategy for overcoming radioresistance and improving clinical outcomes in cancer therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101293"},"PeriodicalIF":21.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898422","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 : 2025-08-16DOI: 10.1016/j.drup.2025.101292
Chun Zhang , Yinhao Chen , Shuncang Zhu , Zuwei Wang , Hongyi Lin , Jinpeng Lu , Haoxiang Zhang , Yueyi Weng , Xiaoxiao Huang , Ge Li , Yongding Wu , Zhiyuan Li , Jianfei Hu , Chengke Xie , Jianlin Lai , Yifeng Tian , Chengyu Liao , Shi Chen
Aim
The persistently high mortality rate of pancreatic ductal adenocarcinoma (PDAC) is largely attributed to the acquired resistance to chemotherapy, particularly gemcitabine. This study aims to elucidate the underlying molecular mechanisms of gemcitabine resistance in PDAC, uncover additional pro-tumorigenic factors contributing to drug resistance, and develop more effective and safer targeted therapeutic strategies against this phenomenon.
Methods
Circular RNA (circRNA) sequencing was employed to identify differentially expressed circRNAs between chemo-sensitive and resistant tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) was utilized to uncover the RNA-binding proteins (RBPs) associated with circular RNA of alpha-1, 3-glucosyltransferase 8 (cALG8). Molecular biology techniques were applied to explore the biological functions and regulatory mechanisms of cALG8 in the context of gemcitabine resistance in PDAC. Single-cell sequencing was performed to reveal changes in the composition of tumor immune microenvironment of pancreatic cancer. Patient-Derived Organoid (PDO) and Patient-Derived Xenograft (PDX) were employed to further validate the molecular mechanisms. Finally, antisense oligonucleotides (ASOs) targeting cALG8 were developed for in vivo use, and their translational therapeutic potential was evaluated in mouse models.
Results
This study identified that cALG8, which is associated with alternative splicing, is highly expressed in gemcitabine-resistant PDAC cells. cALG8 regulates the alternative splicing complex, thereby promoting chemoresistance and immunosuppression in PDAC. Mechanistically, high level of cALG8 functions as a protein scaffold through its 34–85 nt and 109–160 nt regions, creating spatial conditions for CDC-like kinase 1 (CLK1) to phosphorylate serine/arginine-rich splicing factor 7 (SRSF7) at site 231S. This process facilitates the formation of the SRSF7-dependent ataxia-telangiectasia mutated (ATM) kinase variant, ATM203, enhancing the translational efficiency of ATM, and consequently promoting DNA damage repair and immune microenvironment remodeling in PDAC cells to counteract the effects of chemotherapeutic drugs. A cALG8-targeting ASO that disrupts the CLK1-SRSF7 interaction, when combined with gemcitabine and anti-programmed cell death protein (PD)-1 antibody, significantly reduced tumor burden in PDX model, validating its therapeutic translational value.
Conclusion
We demonstrated that the cALG8/CLK1/SRSF7 axis promotes ATM expression by enhancing the splicing of ATM203, thereby facilitating gemcitabine resistance and formation of an immunosuppressive microenvironment in PDAC. This insight aids in the development of drugs targeting chemotherapy resistance induced by DNA damage repair mechanisms in PDAC.
{"title":"Targeting CLK1/SRSF7 axis-dependent alternative splicing sensitizes pancreatic ductal adenocarcinoma to chemotherapy and immunotherapy","authors":"Chun Zhang , Yinhao Chen , Shuncang Zhu , Zuwei Wang , Hongyi Lin , Jinpeng Lu , Haoxiang Zhang , Yueyi Weng , Xiaoxiao Huang , Ge Li , Yongding Wu , Zhiyuan Li , Jianfei Hu , Chengke Xie , Jianlin Lai , Yifeng Tian , Chengyu Liao , Shi Chen","doi":"10.1016/j.drup.2025.101292","DOIUrl":"10.1016/j.drup.2025.101292","url":null,"abstract":"<div><h3>Aim</h3><div>The persistently high mortality rate of pancreatic ductal adenocarcinoma (PDAC) is largely attributed to the acquired resistance to chemotherapy, particularly gemcitabine. This study aims to elucidate the underlying molecular mechanisms of gemcitabine resistance in PDAC, uncover additional pro-tumorigenic factors contributing to drug resistance, and develop more effective and safer targeted therapeutic strategies against this phenomenon.</div></div><div><h3>Methods</h3><div>Circular RNA (circRNA) sequencing was employed to identify differentially expressed circRNAs between chemo-sensitive and resistant tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) was utilized to uncover the RNA-binding proteins (RBPs) associated with circular RNA of alpha-1, 3-glucosyltransferase 8 (cALG8). Molecular biology techniques were applied to explore the biological functions and regulatory mechanisms of cALG8 in the context of gemcitabine resistance in PDAC. Single-cell sequencing was performed to reveal changes in the composition of tumor immune microenvironment of pancreatic cancer. Patient-Derived Organoid (PDO) and Patient-Derived Xenograft (PDX) were employed to further validate the molecular mechanisms. Finally, antisense oligonucleotides (ASOs) targeting cALG8 were developed for in vivo use, and their translational therapeutic potential was evaluated in mouse models.</div></div><div><h3>Results</h3><div>This study identified that cALG8, which is associated with alternative splicing, is highly expressed in gemcitabine-resistant PDAC cells. cALG8 regulates the alternative splicing complex, thereby promoting chemoresistance and immunosuppression in PDAC. Mechanistically, high level of cALG8 functions as a protein scaffold through its 34–85 nt and 109–160 nt regions, creating spatial conditions for CDC-like kinase 1 (CLK1) to phosphorylate serine/arginine-rich splicing factor 7 (SRSF7) at site 231S. This process facilitates the formation of the SRSF7-dependent ataxia-telangiectasia mutated (ATM) kinase variant, ATM203, enhancing the translational efficiency of ATM, and consequently promoting DNA damage repair and immune microenvironment remodeling in PDAC cells to counteract the effects of chemotherapeutic drugs. A cALG8-targeting ASO that disrupts the CLK1-SRSF7 interaction, when combined with gemcitabine and anti-programmed cell death protein (PD)-1 antibody, significantly reduced tumor burden in PDX model, validating its therapeutic translational value.</div></div><div><h3>Conclusion</h3><div>We demonstrated that the cALG8/CLK1/SRSF7 axis promotes ATM expression by enhancing the splicing of ATM203, thereby facilitating gemcitabine resistance and formation of an immunosuppressive microenvironment in PDAC. This insight aids in the development of drugs targeting chemotherapy resistance induced by DNA damage repair mechanisms in PDAC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101292"},"PeriodicalIF":21.7,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144866426","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 : 2025-08-13DOI: 10.1016/j.drup.2025.101291
Yanxia Wang , Fancheng Kong , Xiaohua Situ , Tiantian Yang , Tianqi Sun , Zhongpeng Xie , Pingling Wang , Yu Chen , Neng Jiang , Yu Dong , Zhaofan Luo , Zunfu Ke
Aims
Pancreatic ductal adenocarcinoma (PDAC) remains a daunting malignancy with limited therapeutic options; effective biomarkers are needed to improve its treatment decision-making. The aim of this study is to evaluate the role of homologous recombination deficiency (HRD) in assessing the response to platinum chemotherapy in PDAC.
Methods
A retrospective analysis was conducted on 264 patients diagnosed with PDAC. Tumor tissue samples were subjected to next-generation sequencing (NGS) to assess DNA damage repair (DDR) gene mutation landscape and HRD score. The integrated HRD score was calculated as the unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transition (LST) scores. The associations between HRD status and clinical outcomes in patients receiving platinum treatment were systematically analyzed.
Results
Patients with BRCA1/2 biallelic loss-of-function (BILOF) status and/or an HRD score ≥ 42 were predefined as HRD-positive. According to this HRD status definition, 4.9 % (n = 13) of the 264 patients were identified as HRD-positive, identifying a broader population than using BRCA1/2 BILOF alone (1.9 %, n = 5). Patients with BRCA1/2 mutations (BRCA1/2 m), presented a lower frequency of alteration in genes related to non-homologous end joining (NHEJ) and mismatch repair (MMR) genes than those with BRCA1/2 wild-type (BRCA1/2 wt), with mutations observed in 46.15 % (6/13) of BRCA1/2 m versus 72.91 % (183/251) of BRCA1/2 wt patients. The median HRD score (23) in patients with DNA damage repair (DDR) gene BILOF mutations was notably higher than that in those with non-BILOF mutations in DDR genes (9). HRD-positive patients demonstrated markedly longer progression-free survival (PFS) (median PFS 44.1 months) than HRD-negative patients (median PFS 12.2 months) when the patients received first-line platinum-based adjuvant treatment (P = 0.035). Specifically, patients with BRCA1/2 BILOF exhibited a substantial clinical benefit from platinum therapy, with none of these patients experiencing disease progression or death during follow-up.
Conclusions
BRCA1/2 BILOF plays a crucial role in identifying PDAC patients for first-line platinum-based adjuvant treatment, and HRD positive status, defined by BRCA1/2 BILOF and/or an HRD score ≥ 42, broadens the pool of eligible patients, and helps avoid ineffective treatment due to intrinsic drug resistance.
{"title":"Defining homologous recombination deficiency status in pancreatic ductal adenocarcinoma: Clinical implications for evaluating response to platinum chemotherapy","authors":"Yanxia Wang , Fancheng Kong , Xiaohua Situ , Tiantian Yang , Tianqi Sun , Zhongpeng Xie , Pingling Wang , Yu Chen , Neng Jiang , Yu Dong , Zhaofan Luo , Zunfu Ke","doi":"10.1016/j.drup.2025.101291","DOIUrl":"10.1016/j.drup.2025.101291","url":null,"abstract":"<div><h3>Aims</h3><div>Pancreatic ductal adenocarcinoma (PDAC) remains a daunting malignancy with limited therapeutic options; effective biomarkers are needed to improve its treatment decision-making. The aim of this study is to evaluate the role of homologous recombination deficiency (HRD) in assessing the response to platinum chemotherapy in PDAC.</div></div><div><h3>Methods</h3><div>A retrospective analysis was conducted on 264 patients diagnosed with PDAC. Tumor tissue samples were subjected to next-generation sequencing (NGS) to assess DNA damage repair (DDR) gene mutation landscape and HRD score. The integrated HRD score was calculated as the unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transition (LST) scores. The associations between HRD status and clinical outcomes in patients receiving platinum treatment were systematically analyzed.</div></div><div><h3>Results</h3><div>Patients with <em>BRCA1/2</em> biallelic loss-of-function (BILOF) status and/or an HRD score ≥ 42 were predefined as HRD-positive. According to this HRD status definition, 4.9 % (n = 13) of the 264 patients were identified as HRD-positive, identifying a broader population than using <em>BRCA1/2</em> BILOF alone (1.9 %, n = 5). Patients with <em>BRCA1/2</em> mutations (<em>BRCA1/2 </em><sup>m</sup>), presented a lower frequency of alteration in genes related to non-homologous end joining (NHEJ) and mismatch repair (MMR) genes than those with <em>BRCA1/2</em> wild-type (<em>BRCA1/2 </em><sup>wt</sup>), with mutations observed in 46.15 % (6/13) of <em>BRCA1/2 </em><sup>m</sup> versus 72.91 % (183/251) of <em>BRCA1/2 </em><sup>wt</sup> patients. The median HRD score (23) in patients with DNA damage repair (DDR) gene BILOF mutations was notably higher than that in those with non-BILOF mutations in DDR genes (9). HRD-positive patients demonstrated markedly longer progression-free survival (PFS) (median PFS 44.1 months) than HRD-negative patients (median PFS 12.2 months) when the patients received first-line platinum-based adjuvant treatment (<em>P</em> = 0.035). Specifically, patients with <em>BRCA1/2</em> BILOF exhibited a substantial clinical benefit from platinum therapy, with none of these patients experiencing disease progression or death during follow-up.</div></div><div><h3>Conclusions</h3><div><em>BRCA1/2</em> BILOF plays a crucial role in identifying PDAC patients for first-line platinum-based adjuvant treatment, and HRD positive status, defined by <em>BRCA1/2</em> BILOF and/or an HRD score ≥ 42, broadens the pool of eligible patients, and helps avoid ineffective treatment due to intrinsic drug resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101291"},"PeriodicalIF":21.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144879766","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 : 2025-08-05DOI: 10.1016/j.drup.2025.101289
Nan Gao, Jiaqi Sun, Xiang Li, Yuting Yao, Yujie Hu, Jiani Zhao, Anshan Shan, Jiajun Wang
Antimicrobial peptides (AMPs) have emerged as a promising solution to combat multidrug-resistant (MDR) bacteria. Their unique mechanisms of action reduce the likelihood of resistance development. However, despite their potential, AMPs in clinical trials face significant challenges, including proteolytic degradation and short half-lives during systemic or oral administration. To address these limitations and enhance AMP stability and therapeutic efficacy, several key strategies have been explored. In this review, we summarize recent advances in AMP design, covering: 1) the delivery and formulation of AMPs, including metal-based, polymer-based, and lipid-based delivery systems, as well as the self-assembled nanotechnology of AMPs; 2) the internal modification of AMPs, including stereochemical modification, structural cyclization modification, and terminal modification. This review provides critical insights into AMP optimization, guides the development of future drug candidates, and highlights the interdisciplinary approaches required to accelerate clinical translation.
{"title":"Overcoming delivery challenges of antimicrobial peptides for clinical translation: From nanocarriers to molecular modifications","authors":"Nan Gao, Jiaqi Sun, Xiang Li, Yuting Yao, Yujie Hu, Jiani Zhao, Anshan Shan, Jiajun Wang","doi":"10.1016/j.drup.2025.101289","DOIUrl":"10.1016/j.drup.2025.101289","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs) have emerged as a promising solution to combat multidrug-resistant (MDR) bacteria. Their unique mechanisms of action reduce the likelihood of resistance development. However, despite their potential, AMPs in clinical trials face significant challenges, including proteolytic degradation and short half-lives during systemic or oral administration. To address these limitations and enhance AMP stability and therapeutic efficacy, several key strategies have been explored. In this review, we summarize recent advances in AMP design, covering: 1) the delivery and formulation of AMPs, including metal-based, polymer-based, and lipid-based delivery systems, as well as the self-assembled nanotechnology of AMPs; 2) the internal modification of AMPs, including stereochemical modification, structural cyclization modification, and terminal modification. This review provides critical insights into AMP optimization, guides the development of future drug candidates, and highlights the interdisciplinary approaches required to accelerate clinical translation.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101289"},"PeriodicalIF":21.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809211","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 : 2025-08-05DOI: 10.1016/j.drup.2025.101287
Hengzhou Zhu , Yuanyang Tian , Haoyan Chen , Yiyang Qian , Jiahui Li , Dong Niu , Wenyue Zhao , Yulin Wu , Xian Zhang , Tao Tang , Hu Li , Yan-Fang Xian , Dongdong Sun , Chunhui Jin
Targeting DNA damage response (DDR) pathways has become a promising strategy for overcoming tumor drug resistance, particularly in cancers with DNA repair defects. DDR pathways, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR), are essential for maintaining genomic stability. However, resistance to DDR-targeted therapies, such as PARP inhibitors, often arises due to tumor adaptation through various mechanisms. These include HR pathway restoration, mutations in DDR proteins, altered drug metabolism, and the activation of compensatory repair pathways. This review provides a comprehensive analysis of the molecular mechanisms underlying DDR resistance in tumors and explores the clinical implications of these mechanisms in the context of ongoing therapeutic strategies. We also discuss emerging approaches to overcome DDR resistance, including the development of novel DDR inhibitors, combination therapies, and precision medicine approaches based on biomarkers. Furthermore, we highlight future research directions, focusing on the use of advanced technologies, such as CRISPR screening, single-cell sequencing, and artificial intelligence, to uncover new targets and therapeutic strategies to combat DDR-related drug resistance.
{"title":"Targeting DNA damage response pathways in tumor drug resistance: Mechanisms, clinical implications, and future directions","authors":"Hengzhou Zhu , Yuanyang Tian , Haoyan Chen , Yiyang Qian , Jiahui Li , Dong Niu , Wenyue Zhao , Yulin Wu , Xian Zhang , Tao Tang , Hu Li , Yan-Fang Xian , Dongdong Sun , Chunhui Jin","doi":"10.1016/j.drup.2025.101287","DOIUrl":"10.1016/j.drup.2025.101287","url":null,"abstract":"<div><div>Targeting DNA damage response (DDR) pathways has become a promising strategy for overcoming tumor drug resistance, particularly in cancers with DNA repair defects. DDR pathways, including homologous recombination (HR), non-homologous end joining (NHEJ), base excision repair (BER), and mismatch repair (MMR), are essential for maintaining genomic stability. However, resistance to DDR-targeted therapies, such as PARP inhibitors, often arises due to tumor adaptation through various mechanisms. These include HR pathway restoration, mutations in DDR proteins, altered drug metabolism, and the activation of compensatory repair pathways. This review provides a comprehensive analysis of the molecular mechanisms underlying DDR resistance in tumors and explores the clinical implications of these mechanisms in the context of ongoing therapeutic strategies. We also discuss emerging approaches to overcome DDR resistance, including the development of novel DDR inhibitors, combination therapies, and precision medicine approaches based on biomarkers. Furthermore, we highlight future research directions, focusing on the use of advanced technologies, such as CRISPR screening, single-cell sequencing, and artificial intelligence, to uncover new targets and therapeutic strategies to combat DDR-related drug resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101287"},"PeriodicalIF":21.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809388","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}
Therapeutic resistance remains a significant challenge in breast cancer treatment, often driven by factors such as genetic mutations, dysregulation of receptors and signaling pathways, alterations in drug metabolism and transport, cellular heterogeneity, and modifications in the tumor microenvironment. As a highly heterogeneous and complex disease, breast cancer exhibits distinct molecular and histopathological characteristics, necessitating tailored therapeutic approaches. This article reviews recent advancements in understanding therapy resistance across four major subtypes — Luminal A, Luminal B, HER2-enriched, and triple-negative breast cancer (TNBC) — and explores potential strategies to overcome resistance, providing insights into developing novel therapeutic interventions. Notably, TNBC patients have limited treatment options, with chemotherapy remaining the standard approach and immunotherapy emerging as an adjunct strategy. We concisely overview key mechanisms contributing to therapy resistance and discuss innovative therapeutic strategies, including combination regimens, molecularly targeted therapies, photodynamic therapy, and ferroptosis-inducing treatments. Additionally, we highlight recent advancements in multi-omics data integration and artificial intelligence-driven approaches in breast cancer research. Future efforts should focus on refining predictive models, optimizing combination therapies, and leveraging artificial intelligence to enhance treatment efficacy, ultimately overcoming resistance and improving long-term outcomes for breast cancer patients.
治疗耐药仍然是乳腺癌治疗中的一个重大挑战，通常由基因突变、受体和信号通路失调、药物代谢和转运改变、细胞异质性和肿瘤微环境改变等因素驱动。作为一种高度异质性和复杂性的疾病，乳腺癌表现出独特的分子和组织病理学特征，需要量身定制的治疗方法。本文回顾了四种主要亚型（Luminal A, Luminal B， her2富集和三阴性乳腺癌（TNBC））治疗耐药的最新进展，并探讨了克服耐药的潜在策略，为开发新的治疗干预措施提供了见解。值得注意的是，TNBC患者的治疗选择有限，化疗仍然是标准方法，免疫治疗作为辅助策略出现。我们简要概述了治疗耐药的关键机制，并讨论了创新的治疗策略，包括联合治疗方案、分子靶向治疗、光动力治疗和诱导铁中毒治疗。此外，我们还重点介绍了乳腺癌研究中多组学数据集成和人工智能驱动方法的最新进展。未来的工作应该集中在完善预测模型，优化联合治疗，利用人工智能来提高治疗效果，最终克服耐药，改善乳腺癌患者的长期预后。
{"title":"Drug resistance in breast cancer: Mechanisms and strategies for management","authors":"Guo-Yu Wu , Ming-Zhu Xiao , Wei-Chao Hao , Zhao-Shou Yang , Xin-Ran Liu , Dian-Shuang Xu , Zhong-Xing Peng , Lu-Yong Zhang","doi":"10.1016/j.drup.2025.101288","DOIUrl":"10.1016/j.drup.2025.101288","url":null,"abstract":"<div><div>Therapeutic resistance remains a significant challenge in breast cancer treatment, often driven by factors such as genetic mutations, dysregulation of receptors and signaling pathways, alterations in drug metabolism and transport, cellular heterogeneity, and modifications in the tumor microenvironment. As a highly heterogeneous and complex disease, breast cancer exhibits distinct molecular and histopathological characteristics, necessitating tailored therapeutic approaches. This article reviews recent advancements in understanding therapy resistance across four major subtypes — Luminal A, Luminal B, HER2-enriched, and triple-negative breast cancer (TNBC) — and explores potential strategies to overcome resistance, providing insights into developing novel therapeutic interventions. Notably, TNBC patients have limited treatment options, with chemotherapy remaining the standard approach and immunotherapy emerging as an adjunct strategy. We concisely overview key mechanisms contributing to therapy resistance and discuss innovative therapeutic strategies, including combination regimens, molecularly targeted therapies, photodynamic therapy, and ferroptosis-inducing treatments. Additionally, we highlight recent advancements in multi-omics data integration and artificial intelligence-driven approaches in breast cancer research. Future efforts should focus on refining predictive models, optimizing combination therapies, and leveraging artificial intelligence to enhance treatment efficacy, ultimately overcoming resistance and improving long-term outcomes for breast cancer patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101288"},"PeriodicalIF":21.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809389","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 : 2025-07-31DOI: 10.1016/j.drup.2025.101286
Feifeng Song , Sisi Lin , Tong Xu , Chang Yang , Bold Sharavyn , Hua Naranmandura , Yiwen Zhang , Ping Huang
Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid blasts, leading to hematopoietic suppression and bone marrow failure. Advances in understanding the pathogenesis of AML have fueled the development of precision medicine approaches, with notable successes in targeting specific mutant proteins (e.g., FLT3, IDH1, IDH2), apoptotic regulators (e.g., BCL-2, MCL1), and cell-surface antigens (e.g., CD33, CD123, CD47). These targeted inhibitors exhibit moderate antileukemic activity as monotherapies and their clinical responses are often limited due to the emergence of drug resistance and disease relapse. Nevertheless, synergistic effects have been observed when these agents are combined with conventional chemotherapy or oncogenic pathway inhibitors. This review analyzes the current limitations of targeted therapies and explores multifaceted resistance drivers, encompassing on-target mutations, compensatory signaling pathway activation, drug-efflux mechanisms mediated by metabolic enzymes or transporters, intrinsic adaptive changes, and interactions with the tumor microenvironment. Corresponding therapeutic counterstrategies are also examined, such as mutation-specific molecular targeting, combinatorial suppression of alternative pathways, disruption of intrinsic adaptive responses, and immunotherapeutic approaches. These evolving interventions aim to overcome specific resistance mechanisms and reduce relapse rates. Future research integrating these strategies holds significant promise for addressing persistent challenges in AML management, ultimately advancing treatment paradigms and patient survival.
{"title":"Targeted therapy in acute myeloid leukemia: Resistance and overcoming strategy","authors":"Feifeng Song , Sisi Lin , Tong Xu , Chang Yang , Bold Sharavyn , Hua Naranmandura , Yiwen Zhang , Ping Huang","doi":"10.1016/j.drup.2025.101286","DOIUrl":"10.1016/j.drup.2025.101286","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by uncontrolled proliferation of immature myeloid blasts, leading to hematopoietic suppression and bone marrow failure. Advances in understanding the pathogenesis of AML have fueled the development of precision medicine approaches, with notable successes in targeting specific mutant proteins (e.g., FLT3, IDH1, IDH2), apoptotic regulators (e.g., BCL-2, MCL1), and cell-surface antigens (e.g., CD33, CD123, CD47). These targeted inhibitors exhibit moderate antileukemic activity as monotherapies and their clinical responses are often limited due to the emergence of drug resistance and disease relapse. Nevertheless, synergistic effects have been observed when these agents are combined with conventional chemotherapy or oncogenic pathway inhibitors. This review analyzes the current limitations of targeted therapies and explores multifaceted resistance drivers, encompassing on-target mutations, compensatory signaling pathway activation, drug-efflux mechanisms mediated by metabolic enzymes or transporters, intrinsic adaptive changes, and interactions with the tumor microenvironment. Corresponding therapeutic counterstrategies are also examined, such as mutation-specific molecular targeting, combinatorial suppression of alternative pathways, disruption of intrinsic adaptive responses, and immunotherapeutic approaches. These evolving interventions aim to overcome specific resistance mechanisms and reduce relapse rates. Future research integrating these strategies holds significant promise for addressing persistent challenges in AML management, ultimately advancing treatment paradigms and patient survival.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101286"},"PeriodicalIF":21.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781257","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 : 2025-07-29DOI: 10.1016/j.drup.2025.101285
Rebecca E. Farrell , Kell A. Stelzer , Guo-Jun Liu , Danielle Skropeta
Resistance to existing cancer therapies is a major factor contributing to cancer's persistence as a global health challenge. Abnormal sialylation patterns, commonly due to changes in the expression of sialyltransferases (STs) is a well-established property of tumour cells. There is a growing body of evidence to demonstrate that sialylation is involved in resistance to chemotherapy, targeted therapy, radiotherapy and immunotherapy through a variety of mechanisms that are still being unveiled. In this review, we summarise the reported correlations between aberrant sialylation and cancer therapy resistance, the underlying mechanisms discovered thus far, and progress made in targeting sialylation to enhance responsiveness to cancer treatment.
{"title":"Emerging role of sialylation in cancer therapy resistance: Mechanisms and therapeutic implications","authors":"Rebecca E. Farrell , Kell A. Stelzer , Guo-Jun Liu , Danielle Skropeta","doi":"10.1016/j.drup.2025.101285","DOIUrl":"10.1016/j.drup.2025.101285","url":null,"abstract":"<div><div>Resistance to existing cancer therapies is a major factor contributing to cancer's persistence as a global health challenge. Abnormal sialylation patterns, commonly due to changes in the expression of sialyltransferases (STs) is a well-established property of tumour cells. There is a growing body of evidence to demonstrate that sialylation is involved in resistance to chemotherapy, targeted therapy, radiotherapy and immunotherapy through a variety of mechanisms that are still being unveiled. In this review, we summarise the reported correlations between aberrant sialylation and cancer therapy resistance, the underlying mechanisms discovered thus far, and progress made in targeting sialylation to enhance responsiveness to cancer treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101285"},"PeriodicalIF":21.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781258","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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