Drug Resistance Updates最新文献

{"title":"CD105 blockade restores osimertinib sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer","authors":"Manish Thiruvalluvan ,&nbsp;Sandrine Billet ,&nbsp;Zhenqiu Liu ,&nbsp;Joseph Lownik ,&nbsp;Barliz Waissengrin ,&nbsp;Hyoyoung Kim ,&nbsp;Anton L. Villamejor ,&nbsp;Larry Milshteyn ,&nbsp;Xiamo Li ,&nbsp;Matthew Gayhart ,&nbsp;Manuel Araña ,&nbsp;Kamya Sankar ,&nbsp;Edwin M. Posadas ,&nbsp;Jean Lopategui ,&nbsp;Sungyong You ,&nbsp;Karen L. Reckamp ,&nbsp;Neil A. Bhowmick","doi":"10.1016/j.drup.2025.101237","DOIUrl":"10.1016/j.drup.2025.101237","url":null,"abstract":"<div><h3>Aim</h3><div>To investigate the role of CD105 in mediating drug resistance to EGFR-targeted therapy in non-small cell lung cancer (NSCLC).</div></div><div><h3>Methods</h3><div>Imaging mass cytometry was conducted on 66 NSCLC tumors, 44 of which had EGFR mutations. We correlated clinical variables, including overall survival, with CD105 (endoglin) expression, a co-receptor for bone morphogenetic protein (BMP) signaling. Two osimertinib-resistant EGFR-mutant cell lines were developed to study the effects of EGFR and CD105 disruption. Single cell RNA sequencing of the isogenic parental and osimertinib resistant lines was performed. Additionally, ATAC sequencing and Single Cell ENergetIc metabolism by profiling Translation inHibition analysis (SCENITH) was used to assess promoter chromatin status and glycolytic state.</div></div><div><h3>Results</h3><div>We found a negative correlation between CD105 expression and overall survival in patients. Treatment with osimertinib or EGFR knockdown significantly elevated CD105 expression in EGFR-mutant cell lines. Single-cell RNA sequencing identified a subset of cells with heightened endothelial characteristics and altered pyrimidine metabolism, associated with osimertinib resistance. These cells exhibited a slow-cycling behavior, characterized by elevated chromatin condensation and reduced glycolysis. Combining osimertinib with carotuximab, a CD105 neutralizing antibody, significantly reduced the slow-cycling transcriptomic signature, increased chromatin accessibility, and restored glycolysis compared to osimertinib treatment alone. Mass spectrometry confirmed that carotuximab re-engaged EGFR signaling by coupling it with CD105. Consequently, carotuximab re-sensitized resistant tumors to osimertinib by increasing their mitotic index and ERK signaling in mouse models.</div></div><div><h3>Conclusion</h3><div>Carotuximab effectively reduced the slow-cycling cell population and restored osimertinib sensitivity, offering a promising strategy for managing refractory NSCLC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101237"},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143631721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming cancer therapy resistance: From drug innovation to therapeutics","authors":"Jin-Rui Wei ,&nbsp;Meng-Yi Lu ,&nbsp;Tian-Hua Wei ,&nbsp;Joshua S. Fleishman ,&nbsp;Hui Yu ,&nbsp;Xiao-Li Chen ,&nbsp;Xiang-Tu Kong ,&nbsp;Shan-Liang Sun ,&nbsp;Nian-Guang Li ,&nbsp;Ye Yang ,&nbsp;Hai-Wen Ni","doi":"10.1016/j.drup.2025.101229","DOIUrl":"10.1016/j.drup.2025.101229","url":null,"abstract":"<div><div>One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101229"},"PeriodicalIF":15.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging and senescence: Key players in brain tumor progression and drug resistance","authors":"Chao Zhang ,&nbsp;Neha ,&nbsp;Jiaqi Zhang ,&nbsp;Prashant ,&nbsp;Xiaodie Li ,&nbsp;Sarad Kumar Mishra ,&nbsp;Joshua Fleishman ,&nbsp;Suhel Parvez ,&nbsp;Saurabh Kumar Jha ,&nbsp;Min Huang","doi":"10.1016/j.drup.2025.101228","DOIUrl":"10.1016/j.drup.2025.101228","url":null,"abstract":"<div><div>Aging plays a critical role in the development, progression, and therapeutic challenges associated with brain tumors, particularly glioblastomas (GBM). As the population ages, the incidence of brain tumors, including GBM, increases, with aging emerging as a significant prognostic factor influencing survival outcomes. This review examines the molecular mechanisms linking aging and brain tumor progression, with a specific focus on glioblastomas. We explore how age-related genetic mutations, alterations in cellular pathways, and changes in the tumor microenvironment (TME) contribute to tumorigenesis and treatment resistance. Furthermore, we highlight the impact of key signaling pathways, such as the PI3K/AKT/mTOR, p53, and EGFR/PTEN, which are frequently dysregulated in both aging and brain tumors. Despite the growing recognition of aging as a critical factor in brain tumor biology, therapeutic strategies for elderly patients remain poorly defined, often due to underrepresentation in clinical trials and the complex interplay of comorbidities and treatment side effects. The review also discusses emerging therapeutic approaches, including targeted therapies and immunotherapies, which offer promise for improving treatment outcomes by addressing age-related molecular changes. Finally, we emphasize the importance of personalized treatment strategies and the need for further research to better understand the biological mechanisms underlying the aging-brain tumor relationship, ultimately aiming to enhance clinical management and patient quality of life.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101228"},"PeriodicalIF":15.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGFβ-activated Asporin interacts with STMN1 to promote prostate cancer docetaxel chemoresistance and metastasis by upregulating the Wnt/β-catenin signaling pathway","authors":"Shengdong Ge ,&nbsp;Jinpeng Cen ,&nbsp;Xiaofeng Liu ,&nbsp;Yaying Hong ,&nbsp;Yuting Tang ,&nbsp;Yuzhong Yu ,&nbsp;Haolin Li ,&nbsp;Tao Xie ,&nbsp;Chong Wang ,&nbsp;Maoping Cai ,&nbsp;Yang Qiu ,&nbsp;Xianzi Zeng ,&nbsp;Tianming Peng ,&nbsp;Qu Li ,&nbsp;Qianyi Li ,&nbsp;Xingcheng Wu ,&nbsp;Xian-Lu Song ,&nbsp;Shan-Chao Zhao","doi":"10.1016/j.drup.2025.101227","DOIUrl":"10.1016/j.drup.2025.101227","url":null,"abstract":"<div><h3>Aims</h3><div>Prostate cancer (PCa) remains a significant challenge in oncology due to high rates of drug resistance following standard treatment with docetaxel-based chemotherapy. Asporin (ASPN) has been regarded as an oncogene and its upregulation is closely associated with malignant behavior and poor prognosis in multiple cancers. Studies indicated that abnormal activation of the Wnt/β-catenin signaling pathway is prevalent in PCa. This study investigated the important role of ASPN in regulating Wnt/β-catenin signaling pathway in docetaxel resistance and metastasis of PCa.</div></div><div><h3>Methods</h3><div>The impacts of ASPN on the docetaxel chemoresistance and metastasis of PCa cells were investigated in vitro and in vivo assays. Lastly, the underlying mechanism of ASPN was revealed by Western blot, protein immunocoprecipitation, Immunofluorescence, Immunohistochemical staining, liquid chromatography-mass spectrometry, and rescue experiments.</div></div><div><h3>Results</h3><div>In present study, we reported that ASPN is highly expressed in PCa cells and tissues. Functional and molecular analyses showed that ASPN is activated by TGFβ and interacts with STMN1. ASPN increases the expression of β-catenin and promotes its nuclear accumulation by mediating the activation of the Wnt/β-catenin signaling pathway, thereby enhancing the stemness and epithelial-mesenchymal transition (EMT) of PCa cells, ultimately facilitating the docetaxel resistance and metastasis of PCa cells.</div></div><div><h3>Conclusions</h3><div>Our findings identify ASPN as a novel upstream regulatory factor of Wnt/β-catenin signaling pathway, suggesting that targeting the ASPN/STMN1/β-catenin axis could be a promising strategy for PCa intervention.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101227"},"PeriodicalIF":15.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel insights into taxane pharmacology: An update on drug resistance mechanisms, immunomodulation and drug delivery strategies","authors":"Giovanni Luca Beretta ,&nbsp;Giuliana Cassinelli ,&nbsp;Giacomina Rossi ,&nbsp;Amalia Azzariti ,&nbsp;Iléana Corbeau ,&nbsp;Diego Tosi ,&nbsp;Paola Perego","doi":"10.1016/j.drup.2025.101223","DOIUrl":"10.1016/j.drup.2025.101223","url":null,"abstract":"<div><div>Taxanes are effective in several solid tumors. Paclitaxel, the main clinically available taxane, was approved in the early nineties, for the treatment of ovarian cancer and later on, together with the analogs docetaxel and cabazitaxel, for other malignancies. By interfering with microtubule function and impairing the separation of sister cells at mitosis, taxanes act as antimitotic agents, thereby counteracting the high proliferation rate of cancer cells. The action of taxanes goes beyond their antimitotic function because their main cellular targets, the microtubules, participate in multiple processes such as intracellular transport and cell shape maintenance. The clinical efficacy of taxanes is limited by the development of multiple resistance mechanisms. Among these, extracellular vesicles have emerged as new players. In addition, taxane metronomic schedules shows an impact on the tumor microenvironment reflected by antiangiogenic and immunomodulatory effects, an aspect of growing interest considering their inclusion in treatment regimens with immunotherapeutics. Preclinical studies have paved the bases for synergistic combinations of taxanes both with conventional and targeted agents. A variety of drug delivery strategies have provided novel opportunities to increase the drug activity. The ability of taxanes to orchestrate different cellular effects amenable to modulation suggests novel options to improve cures in lethal malignancies.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101223"},"PeriodicalIF":15.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143611106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methotrexate resistance and its regulatory mechanisms in pediatric tumors and beyond","authors":"Jing Nie ,&nbsp;Lantian Huang ,&nbsp;Yan Shen ,&nbsp;Hongai Pan ,&nbsp;Siwan Wang ,&nbsp;Huawei Zhao ,&nbsp;Peng Gao ,&nbsp;Jufei Yang ,&nbsp;Xiaojun Huang ,&nbsp;Su Zeng ,&nbsp;Jing Miao","doi":"10.1016/j.drup.2025.101225","DOIUrl":"10.1016/j.drup.2025.101225","url":null,"abstract":"<div><div>Methotrexate (MTX) is a critical antimetabolite drug in treating various pediatric diseases, including acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), brain tumors, osteosarcoma, inflammatory myofibroblastic tumor (IMT), juvenile scleroderma (JS), and juvenile idiopathic arthritis (JIA). MTX acts as a folate antagonist by inhibiting dihydrofolate reductase (DHFR), an enzyme essential for the synthesis of tetrahydrofolate. This disruption impairs DNA synthesis, repair, and cellular replication, particularly affecting rapidly dividing cells. Despite its efficacy, MTX resistance poses significant challenges, particularly in pediatric oncology, where it undermines the ability to achieve sustained therapeutic effects, resulting in reduced therapeutic efficacy and poor prognosis. The mechanisms of MTX resistance encompassed reduced enzyme activity pivotal for MTX metabolism, enhanced expression of efflux transporters, genetic variations, and alterations in signaling pathways. Multifaceted strategies have been explored to overcome MTX resistance. Combination therapies with ginger extract, gold nanoparticles, and arsenic trioxide (ATO) have been investigated to augment MTX’s cytotoxic effects. Synergies with mTOR inhibitors and MDM2 inhibitors have demonstrated enhanced outcomes in ALL. In JIA, targeting ATP-binding cassette (ABC) transporters and modulating transforming growth factor‑β (TGF-β) signaling pathways have emerged as promising approaches. For osteosarcoma, emphasis on autophagy pathways and non-coding RNAs influencing chemotherapy sensitivity could enhance MTX effectiveness. This review delineates MTX's therapeutic roles, elucidates its resistance mechanisms, and discusses current and potential strategies for managing MTX resistance to bolster treatment effectiveness in pediatric tumors and other diseases. This knowledge base could underpin further research and development of personalized treatments to optimize MTX's clinical benefits.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101225"},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer","authors":"Muhammad Zubair Saleem ,&nbsp;Ruyi Huang ,&nbsp;Yingying Huang ,&nbsp;Xin Guo ,&nbsp;Yang Liu ,&nbsp;Miao Gao ,&nbsp;Yinjuan Fan ,&nbsp;Zhe-Sheng Chen ,&nbsp;Zun-Fu Ke ,&nbsp;Shengnan Ye ,&nbsp;Jianhua Xu","doi":"10.1016/j.drup.2025.101226","DOIUrl":"10.1016/j.drup.2025.101226","url":null,"abstract":"<div><h3>Aims</h3><div>TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast cancer cells by targeting TRAP1.</div></div><div><h3>Methods</h3><div>Breast cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect <em>in vivo</em> was investigated with mouse tumor model.</div></div><div><h3>Results</h3><div>In hypoxia and glucose deprivation, breast cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent cancer cells by inducing mitochondrial apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising <em>in vivo</em> anticancer efficacy which was particularly related to OXPHOS inhibition.</div></div><div><h3>Conclusions</h3><div>C210 eliminates DOX-resistant quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101226"},"PeriodicalIF":15.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143611105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma","authors":"Zhongyan Zhang ,&nbsp;Qi Zhou ,&nbsp;Zhenchong Li ,&nbsp;Fuxin Huang ,&nbsp;Ke Mo ,&nbsp;Cheng Shen ,&nbsp;Xing Niu ,&nbsp;Baohua Hou ,&nbsp;Chuanzhao Zhang ,&nbsp;Shanzhou Huang","doi":"10.1016/j.drup.2025.101224","DOIUrl":"10.1016/j.drup.2025.101224","url":null,"abstract":"<div><h3>Aims</h3><div>Emerging resistance to Lenvatinib, which is used as a first-line agent for the treatment of advanced hepatocellular carcinoma (HCC), is still a concern. The aim of this study was to determine core factors of Lenvatinib resistance (LR) and their underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>CRISPR screening in HCC cells was conducted, which identified E3 ubiquitin ligase deltex 2 (DTX2) as a core LR-related gene. <em>In vivo</em> and <em>in vitro</em> models were used to clarify the function of DTX2 on LR and ferroptosis. The upstream regulators and downstream effectors of DTX2 were identified, revealing its complex regulatory network.</div></div><div><h3>Results</h3><div>DTX2 promoted anti-ferroptosis in LR HCC cells via downregulating the peroxisomal β-oxidation enzyme HSD17B4. DTX2 induced the ubiquitination-mediated degradation of HSD17B4, resulting in lipid metabolism changes that were associated mainly with docosahexaenoic acid (DHA)-containing PUFAs. Notably, DHA supplements could reverse DTX2-induced anti-ferroptosis and LR. Mechanistically, we uncovered that DTX2 ubiquitinated the HSD17B4 SCP structural domain through its RING structural domain and ubiquitinated the K645 site. The upregulation of DTX2 expression was mediated by JAK2-STAT3 pathway activation. The aberrant activation of STAT3 in acquired LR promoted DTX2 transcription and negatively regulated peroxisomal β-oxidation via K48-ubiquitinated HSD17B4 and decreased DHA-phospholipids levels, leading to the suppression of Lenvatinib-induced ferroptosis in HCC.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that DTX2 attenuates Lenvatinib-induced ferroptosis by inhibiting DHA biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in HCC. The combination of DHA with Lenvatinib could be a promising therapeutic strategy for patients with LR HCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101224"},"PeriodicalIF":15.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The combination of flaxseed lignans and PD-1/ PD-L1 inhibitor inhibits breast cancer growth via modulating gut microbiome and host immunity","authors":"Hao Wu ,&nbsp;Jiena Liu ,&nbsp;Xing-Hua Zhang ,&nbsp;Shengye Jin ,&nbsp;Ping Li ,&nbsp;Huidi Liu ,&nbsp;Liuying Zhao ,&nbsp;Jianyu Wang ,&nbsp;Shilu Zhao ,&nbsp;Hong-Da Tian ,&nbsp;Jin-Ru Lai ,&nbsp;Yi Hao ,&nbsp;Gui-Rong Liu ,&nbsp;Kaijian Hou ,&nbsp;Meisi Yan ,&nbsp;Shu-Lin Liu ,&nbsp;Da Pang","doi":"10.1016/j.drup.2025.101222","DOIUrl":"10.1016/j.drup.2025.101222","url":null,"abstract":"<div><h3>Background</h3><div>Patients with breast cancer (BC) who benefit from the PD-1/PD-L1 inhibitor (PDi) is limited, necessitating novel strategies to improve immunotherapy efficacy of BC. Here we aimed to investigate the inhibitory effects of flaxseed lignans (FL) on the biological behaviors of BC and evaluate the roles of FL in enhancing the anticancer effects of PDi.</div></div><div><h3>Methods</h3><div>HPLC was used to detect the content of enterolactone (ENL), the bacterial transformation product of FL. Transcript sequencing was performed and identified CD38 as a downstream target gene of ENL. CD38-overexpressing cells were constructed and cell proliferation, colony formation, wound healing and transwell assays were used to assess the function of ENL/CD38 axis on BC cells <em>in vitro</em>. Multiplexed immunohistochemistry (mIHC) and CyTOF were used to detect the changes of the tumor immune microenvironment (TIM). 16S rDNA sequencing was used to explore the changes of gut microbiota in mice. A series of <em>in vivo</em> experiments were conducted to investigate the anticancer effects and mechanisms of FL and PDi.</div></div><div><h3>Results</h3><div>FL was converted to ENL by gut microbiota and FL administration inhibited the progression of BC. ENL inhibited the malignant behaviors of BC by downregulating CD38, a key gene associated with immunosuppression and PD-1/PD-L1 blockade resistance. The mIHC assay revealed that FL administration enhanced CD3⁺, CD4⁺ and CD8⁺ cells and reduced F4/80⁺ cells in TIM. CyTOF confirmed the regulatory effects of FL and FL in combination with PDi (FLcPDi) on TIM. In addition, 16S rDNA analysis demonstrated that FLcPDi treatment significantly elevated the abundance of <em>Akkermansia</em> and, importantly, <em>Akkermansia</em> administration enhanced the response to PDi in mice treated with antibiotics.</div></div><div><h3>Conclusions</h3><div>The FL/ENL/CD38 axis inhibited BC progression. FL enhanced the anticancer effects of PDi by modulating gut microbiota and host immunity.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"80 ","pages":"Article 101222"},"PeriodicalIF":15.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resistance to immunotherapy in non-small cell lung cancer: Unraveling causes, developing effective strategies, and exploring potential breakthroughs","authors":"Shuang Dong ,&nbsp;Xiaoyu Li ,&nbsp;Qing Huang ,&nbsp;Yuanxiang Li ,&nbsp;Jinjiao Li ,&nbsp;Xianmin Zhu ,&nbsp;Chang Xue ,&nbsp;Runzhi Chen ,&nbsp;Yuan Zeng ,&nbsp;Jingyi Wu ,&nbsp;Yi Zhong ,&nbsp;Sheng Hu","doi":"10.1016/j.drup.2025.101215","DOIUrl":"10.1016/j.drup.2025.101215","url":null,"abstract":"<div><div>Over the last two decades, advancements in deciphering the intricate interactions between oncology and immunity have fueled a meteoric rise in immunotherapy for non-small cell lung cancer, typified by an explosive growth of immune checkpoint inhibitors. However, resistance to immunotherapy remains inevitable. Herein we unravel the labyrinthine mechanisms of resistance to immunotherapy, characterized by their involvement of nearly all types of cells within the body, beyond the extrinsic cancer cells, and importantly, such cells are not only (inhibitory or excitatory, or both) signal recipients but also producers, acting in a context-dependent manner. At the molecular level, these mechanisms underlie genetic and epigenetic aberrations, which are regulated by or regulate various protein kinases, growth factors, and cytokines with inherently dynamic and spatially heterogeneous properties. Additionally, macroscopic factors such as nutrition, comorbidities, and the microbiome within and around organs or tumor cells are involved. Therefore, developing therapeutic strategies combined with distinct action informed by preclinical, clinical, and real-world evidence, such as radiotherapy, chemotherapy, targeted therapy, antibody-drug conjugates, oncolytic viruses, and cell-based therapies, may stand as a judicious reality, although the ideality is to overcome resistance point-by-point through a novel drug. Notably, we highlight a realignment of treatment aims, moving the primary focus from eliminating cancer cells -- such as through chemotherapy and radiotherapy -- to promoting immune modulation and underscore the value of regulating various components within the host macro- or micro-environment, as their effects, even if seemingly minimal, can cumulatively contribute to visible clinical benefit when applied in combination with ICIs. Lastly, this review also emphasizes the current hurdles scattered throughout preclinical and clinical studies, and explores evolving directions in the landscape of immunotherapy for NSCLC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101215"},"PeriodicalIF":15.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601583","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}