Drug Resistance Updates最新文献

{"title":"FAT1 as a tumor mutation burden specific gene affects the immunotherapy effect in head and neck squamous cell cancer","authors":"Haotian Cao ,&nbsp;Tianjun Lan ,&nbsp;Shijia Kuang ,&nbsp;Liansheng Wang ,&nbsp;Jintao Li ,&nbsp;Qunxin Li ,&nbsp;Yanyan Li ,&nbsp;Qiuping Xu ,&nbsp;Qian Chen ,&nbsp;Shuwei Ren ,&nbsp;Chunhong Lan ,&nbsp;Nengtai Ouyang ,&nbsp;Jianwei Liao ,&nbsp;Yongsheng Huang ,&nbsp;Jinsong Li","doi":"10.1016/j.drup.2024.101095","DOIUrl":"10.1016/j.drup.2024.101095","url":null,"abstract":"<div><h3>Background</h3><p>Response to immunotherapy is the main challenge of head and neck squamous cancer (HNSCC) treatment. Previous studies have indicated that tumor mutational burden (TMB) is associated with prognosis, but it is not always a precise index. Hence, investigating specific genetic mutations and tumor microenvironment (TME) changes in TMB-high patients is essential for precision therapy of HNSCC.</p></div><div><h3>Methods</h3><p>A total of 33 HNSCC patients were enrolled in this study. We calculated the TMB score based on next-generation sequencing (NGS) sequencing and grouped these patients based on TMB score. Then, we examined the immune microenvironment of HNSCC using assessments of the bulk transcriptome and the single-cell RNA sequence (scRNA-seq) focusing on the molecular nature of TMB and mutations in HNSCC from our cohort. The association of the mutation pattern and TMB was analyzed in The Cancer Genome Atlas (TCGA) and validated by our cohort.</p></div><div><h3>Results</h3><p>33 HNSCC patients were divided into three groups (TMB-low, -medium, and -high) based on TMB score. In the result of 520-gene panel sequencing data, we found that FAT1 and LRP1B mutations were highly prevalent in TMB-high patients. FAT1 mutations are associated with resistance to immunotherapy in HNSCC patients. This involves many metabolism-related pathways like RERE, AIRE, HOMER1, etc. In the scRNA-seq data, regulatory T cells (Tregs), monocytes, and DCs were found mainly enriched in TMB-high samples.</p></div><div><h3>Conclusion</h3><p>Our analysis unraveled the FAT1 gene as an assistant predictor when we use TMB as a biomarker of drug resistance in HNSCC. Tregs, monocytes, and dendritic cells (DCs) were found mainly enriched in TMB-high samples.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141581475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of NMCR-3, NMCR-4 and NMCR-5, three novel non-mobile colistin resistance determinants: Implications for MCR-3, MCR-7, and MCR-5 progenitors, respectively","authors":"Yating Guo ,&nbsp;Geng Zou ,&nbsp;Anusak Kerdsin ,&nbsp;Constance Schultsz ,&nbsp;Can Hu ,&nbsp;Weicheng Bei ,&nbsp;Huanchun Chen ,&nbsp;Jinquan Li ,&nbsp;Yang Zhou","doi":"10.1016/j.drup.2024.101088","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101088","url":null,"abstract":"<div><p>In this study, the progenitors of MCR-3, MCR-7 and MCR-5, namely NMCR-3, NMCR-4 and NMCR-5, were firstly discovered and indicating <em>Aeromonas</em> was a natural reservoir for MCR-3 and MCR-7. Furthermore, different evolutionary models for MCR-3, MCR-7 and MCR-5 were proposed.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000463/pdfft?md5=c9ed71f1b7ae173d499d611ebb7b61a1&pid=1-s2.0-S1368764624000463-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140913941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spotlight on ideal target antigens and resistance in antibody-drug conjugates: Strategies for competitive advancement","authors":"Mingxia Jiang ,&nbsp;Qiao Li ,&nbsp;Binghe Xu","doi":"10.1016/j.drup.2024.101086","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101086","url":null,"abstract":"<div><p>Antibody-drug conjugates (ADCs) represent a novel and promising approach in targeted therapy, uniting the specificity of antibodies that recognize specific antigens with payloads, all connected by the stable linker. These conjugates combine the best targeted and cytotoxic therapies, offering the killing effect of precisely targeting specific antigens and the potent cell-killing power of small molecule drugs. The targeted approach minimizes the off-target toxicities associated with the payloads and broadens the therapeutic window, enhancing the efficacy and safety profile of cancer treatments. Within precision oncology, ADCs have garnered significant attention as a cutting-edge research area and have been approved to treat a range of malignant tumors. Correspondingly, the issue of resistance to ADCs has gradually come to the fore. Any dysfunction in the steps leading to the ADCs' action within tumor cells can lead to the development of resistance. A deeper understanding of resistance mechanisms may be crucial for developing novel ADCs and exploring combination therapy strategies, which could further enhance the clinical efficacy of ADCs in cancer treatment. This review outlines the brief historical development and mechanism of ADCs and discusses the impact of their key components on the activity of ADCs. Furthermore, it provides a detailed account of the application of ADCs with various target antigens in cancer therapy, the categorization of potential resistance mechanisms, and the current state of combination therapies. Looking forward, breakthroughs in overcoming technical barriers, selecting differentiated target antigens, and enhancing resistance management and combination therapy strategies will broaden the therapeutic indications for ADCs. These progresses are anticipated to advance cancer treatment and yield benefits for patients.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140645896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneity of SOS response expression in clinical isolates of Escherichia coli influences adaptation to antimicrobial stress","authors":"Sara Diaz-Diaz ,&nbsp;Andrea Garcia-Montaner ,&nbsp;Roberta Vanni ,&nbsp;Marina Murillo-Torres ,&nbsp;Esther Recacha ,&nbsp;Marina R. Pulido ,&nbsp;Maria Romero-Muñoz ,&nbsp;Fernando Docobo-Pérez ,&nbsp;Alvaro Pascual ,&nbsp;Jose Manuel Rodriguez-Martinez","doi":"10.1016/j.drup.2024.101087","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101087","url":null,"abstract":"<div><p>In recent years, new evidence has shown that the SOS response plays an important role in the response to antimicrobials, with involvement in the generation of clinical resistance. Here we evaluate the impact of heterogeneous expression of the SOS response in clinical isolates of <em>Escherichia coli</em> on response to the fluoroquinolone, ciprofloxacin. <em>In silico</em> analysis of whole genome sequencing data showed remarkable sequence conservation of the SOS response regulators, RecA and LexA. Despite the genetic homogeneity, our results revealed a marked differential heterogeneity in SOS response activation, both at population and single-cell level, among clinical isolates of <em>E. coli</em> in the presence of subinhibitory concentrations of ciprofloxacin. Four main stages of SOS response activation were identified and correlated with cell filamentation. Interestingly, there was a correlation between clinical isolates with higher expression of the SOS response and further progression to resistance. This heterogeneity in response to DNA damage repair (mediated by the SOS response) and induced by antimicrobial agents could be a new factor with implications for bacterial evolution and survival contributing to the generation of antimicrobial resistance.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000451/pdfft?md5=d62973c9569c8b14b7be721203fa08fd&pid=1-s2.0-S1368764624000451-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140650582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential targets and therapeutics for cancer stem cell-based therapy against drug resistance in hepatocellular carcinoma","authors":"Hongxing Zhao ,&nbsp;Yuhang Ling ,&nbsp;Jie He ,&nbsp;Jinling Dong ,&nbsp;Qinliang Mo ,&nbsp;Yao Wang ,&nbsp;Ying Zhang ,&nbsp;Hongbin Yu ,&nbsp;Chengwu Tang","doi":"10.1016/j.drup.2024.101084","DOIUrl":"10.1016/j.drup.2024.101084","url":null,"abstract":"<div><p>Hepatocellular carcinoma (HCC) is the most common digestive malignancyin the world, which is frequently diagnosed at late stage with a poor prognosis. For most patients with advanced HCC, the therapeutic options arelimiteddue to cancer occurrence of drug resistance. Hepatic cancer stem cells (CSCs) account for a small subset of tumor cells with the ability of self-renewal and differentiationin HCC. It is widely recognized that the presence of CSCs contributes to primary and acquired drug resistance. Therefore, hepatic CSCs-targeted therapy is considered as a promising strategy to overcome drug resistance and improve therapeutic outcome in HCC. In this article, we review drug resistance in HCC and provide a summary of potential targets for CSCs-based therapy. In addition, the development of CSCs-targeted therapeuticsagainst drug resistance in HCC is summarized in both preclinical and clinical trials. The in-depth understanding of CSCs-related drug resistance in HCC will favor optimization of the current therapeutic strategies and gain encouraging therapeutic outcomes.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140608359","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":"Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy","authors":"Qin Zhou ,&nbsp;Xinyi Tu ,&nbsp;Xiaonan Hou ,&nbsp;Jia Yu ,&nbsp;Fei Zhao ,&nbsp;Jinzhou Huang ,&nbsp;Jake Kloeber ,&nbsp;Anna Olson ,&nbsp;Ming Gao ,&nbsp;Kuntian Luo ,&nbsp;Shouhai Zhu ,&nbsp;Zheming Wu ,&nbsp;Yong Zhang ,&nbsp;Chenyu Sun ,&nbsp;Xiangyu Zeng ,&nbsp;Kenneth J. Schoolmeester ,&nbsp;John S. Weroha ,&nbsp;Xiwen Hu ,&nbsp;Yanxia Jiang ,&nbsp;Liewei Wang ,&nbsp;Zhenkun Lou","doi":"10.1016/j.drup.2024.101085","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101085","url":null,"abstract":"<div><p>Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140607341","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":"Expansion and transmission dynamics of high risk carbapenem-resistant Klebsiella pneumoniae subclones in China: An epidemiological, spatial, genomic analysis","authors":"Qi Wang ,&nbsp;Ruobing Wang ,&nbsp;Shuyi Wang ,&nbsp;Anru Zhang ,&nbsp;Qiaoyan Duan ,&nbsp;Shijun Sun ,&nbsp;Longyang Jin ,&nbsp;Xiaojuan Wang ,&nbsp;Yawei Zhang ,&nbsp;Chunlei Wang ,&nbsp;Haiquan Kang ,&nbsp;Zhijie Zhang ,&nbsp;Kang Liao ,&nbsp;Yinghui Guo ,&nbsp;Liang Jin ,&nbsp;Zhiwu Liu ,&nbsp;Chunxia Yang ,&nbsp;Hui Wang ,&nbsp;on behalf of the China Carbapenem-Resistant Enterobacterales (CRE) Network","doi":"10.1016/j.drup.2024.101083","DOIUrl":"10.1016/j.drup.2024.101083","url":null,"abstract":"<div><h3>Aims</h3><p>Carbapenem-resistant <em>Klebsiella pneumonia</em> (CRKP) is a global threat that varies by region. The global distribution, evolution, and clinical implications of the ST11 CRKP clone remain obscure.</p></div><div><h3>Methods</h3><p>We conducted a multicenter molecular epidemiological survey using isolates obtained from 28 provinces and municipalities across China between 2011 and 2021. We integrated sequences from public databases and performed genetic epidemiology analysis of ST11 CRKP.</p></div><div><h3>Results</h3><p>Among ST11 CRKP, KL64 serotypes exhibited considerable expansion, increasing from 1.54% to 46.08% between 2011 and 2021. Combining our data with public databases, the phylogenetic and phylogeography analyses indicated that ST11 CRKP appeared in the Americas in 1996 and spread worldwide, with key clones progressing from China’s southeastern coast to the inland by 2010. Global phylogenetic analysis showed that ST11 KL64 CRKP has evolved to a virulent, resistant clade with notable regional spread. Single-nucleotide polymorphism (SNP) analysis identified BMPPS (<em>bmr3, mltC, pyrB, ppsC,</em> and <em>sdaC</em>) as a key marker for this clade. The BMPPS SNP clade is associated with high mortality and has strong anti-phagocytic and competitive traits <em>in vitro</em>.</p></div><div><h3>Conclusions</h3><p>The high-risk ST11 KL64 CRKP subclone showed strong expansion potential and survival advantages, probably owing to genetic factors.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000414/pdfft?md5=19e3e9a36084d1d1417245bb9050b0d4&pid=1-s2.0-S1368764624000414-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140406228","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":"Advances in molecular targeted drugs in combination with CAR-T cell therapy for hematologic malignancies","authors":"Yuxian Huang ,&nbsp;Yinjie Qin ,&nbsp;Yingzhi He ,&nbsp;Dezhi Qiu ,&nbsp;Yeqin Zheng ,&nbsp;Jiayue Wei ,&nbsp;Lenghe Zhang ,&nbsp;Dong‑Hua Yang ,&nbsp;Yuhua Li","doi":"10.1016/j.drup.2024.101082","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101082","url":null,"abstract":"<div><p>Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000402/pdfft?md5=af65de610b056964260cd200f4500120&pid=1-s2.0-S1368764624000402-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140342459","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":"Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome","authors":"Alberto Diaz-Jimenez ,&nbsp;Maria Ramos ,&nbsp;Barbara Helm ,&nbsp;Sara Chocarro ,&nbsp;Dario Lucas Frey ,&nbsp;Shubham Agrawal ,&nbsp;Kalman Somogyi ,&nbsp;Ursula Klingmüller ,&nbsp;Junyan Lu ,&nbsp;Rocio Sotillo","doi":"10.1016/j.drup.2024.101081","DOIUrl":"10.1016/j.drup.2024.101081","url":null,"abstract":"<div><p>Precision oncology has revolutionized the treatment of ALK-positive lung cancer with targeted therapies. However, an unmet clinical need still to address is the treatment of refractory tumors that contain drug-induced resistant mutations in the driver oncogene or exhibit resistance through the activation of diverse mechanisms. In this study, we established mouse tumor-derived cell models representing the two most prevalent <em>EML4-ALK</em> variants in human lung adenocarcinomas and characterized their proteomic profiles to gain insights into the underlying resistance mechanisms. We showed that <em>Eml4-Alk</em> variant 3 confers a worse response to ALK inhibitors, suggesting its role in promoting resistance to targeted therapy. In addition, proteomic analysis of brigatinib-treated cells revealed the upregulation of SRC kinase, a protein frequently activated in cancer. Co-targeting of ALK and SRC showed remarkable inhibitory effects in both ALK-driven murine and ALK-patient-derived lung tumor cells. This combination induced cell death through a multifaceted mechanism characterized by profound perturbation of the (phospho)proteomic landscape and a synergistic suppressive effect on the mTOR pathway. Our study demonstrates that the simultaneous inhibition of ALK and SRC can potentially overcome resistance mechanisms and enhance clinical outcomes in ALK-positive lung cancer patients.</p></div><div><h3>One Sentence Summary</h3><p>Co-targeting ALK and SRC enhances ALK inhibitor response in lung cancer by affecting the proteomic profile, offering hope for overcoming resistance and improving clinical outcomes.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000396/pdfft?md5=280130d588930412fb73ff68067c3adf&pid=1-s2.0-S1368764624000396-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140182568","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":"Circumventing drug resistance in gastric cancer: A spatial multi-omics exploration of chemo and immuno-therapeutic response dynamics","authors":"Gang Che ,&nbsp;Jie Yin ,&nbsp;Wankun Wang ,&nbsp;Yandong Luo ,&nbsp;Yiran Chen ,&nbsp;Xiongfei Yu ,&nbsp;Haiyong Wang ,&nbsp;Xiaosun Liu ,&nbsp;Zhendong Chen ,&nbsp;Xing Wang ,&nbsp;Yu Chen ,&nbsp;Xujin Wang ,&nbsp;Kaicheng Tang ,&nbsp;Jiao Tang ,&nbsp;Wei Shao ,&nbsp;Chao Wu ,&nbsp;Jianpeng Sheng ,&nbsp;Qing Li ,&nbsp;Jian Liu","doi":"10.1016/j.drup.2024.101080","DOIUrl":"10.1016/j.drup.2024.101080","url":null,"abstract":"<div><h3>Background</h3><p>Gastric Cancer (GC) characteristically exhibits heterogeneous responses to treatment, particularly in relation to immuno plus chemo therapy, necessitating a precision medicine approach. This study is centered around delineating the cellular and molecular underpinnings of drug resistance in this context.</p></div><div><h3>Methods</h3><p>We undertook a comprehensive multi-omics exploration of postoperative tissues from GC patients undergoing the chemo and immuno-treatment regimen. Concurrently, an image deep learning model was developed to predict treatment responsiveness.</p></div><div><h3>Results</h3><p>Our initial findings associate apical membrane cells with resistance to fluorouracil and oxaliplatin, critical constituents of the therapy. Further investigation into this cell population shed light on substantial interactions with resident macrophages, underscoring the role of intercellular communication in shaping treatment resistance. Subsequent ligand-receptor analysis unveiled specific molecular dialogues, most notably TGFB1-HSPB1 and LTF-S100A14, offering insights into potential signaling pathways implicated in resistance. Our SVM model, incorporating these multi-omics and spatial data, demonstrated significant predictive power, with AUC values of 0.93 and 0.84 in the exploration and validation cohorts respectively. Hence, our results underscore the utility of multi-omics and spatial data in modeling treatment response.</p></div><div><h3>Conclusion</h3><p>Our integrative approach, amalgamating mIHC assays, feature extraction, and machine learning, successfully unraveled the complex cellular interplay underlying drug resistance. This robust predictive model may serve as a valuable tool for personalizing therapeutic strategies and enhancing treatment outcomes in gastric cancer.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":24.3,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140182564","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}