Drug Resistance Updates最新文献

{"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":"74 ","pages":"Article 101080"},"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}

{"title":"Targeted dual degradation of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models","authors":"Lu Yang ,&nbsp;Arup Bhattacharya ,&nbsp;Darrell Peterson ,&nbsp;Yun Li ,&nbsp;Xiaozhuo Liu ,&nbsp;Elisabetta Marangoni ,&nbsp;Valentina Robila ,&nbsp;Yuesheng Zhang","doi":"10.1016/j.drup.2024.101078","DOIUrl":"10.1016/j.drup.2024.101078","url":null,"abstract":"<div><h3>Aims</h3><p>Human epidermal growth factor receptor 2 (HER2) is an oncogenic receptor tyrosine kinase amplified in approximately 20% of breast cancer (BC). HER2-targeted therapies are the linchpin of treating HER2-positive BC. However, drug resistance is common, and the main resistance mechanism is unknown. We tested the hypothesis that drug resistance results mainly from inadequate or lack of inhibition of HER2 and its family member epidermal growth factor receptor (EGFR).</p></div><div><h3>Methods</h3><p>We used clinically relevant cell and tumor models to assess the impact of targeted degradation of HER2 and EGFR on trastuzumab resistance. Trastuzumab is the most common clinically used HER2 inhibitor. Targeted degradation of HER2 and EGFR was achieved using recombinant human protein PEPD^G278D, which binds to the extracellular domains of the receptors. siRNA knockdown was used to assess the relative importance of EGFR and HER2 in trastuzumab resistance.</p></div><div><h3>Results</h3><p>Both HER2 and EGFR are overexpressed in all trastuzumab-resistant HER2-positive BC cell and tumor models and that all trastuzumab-resistant models are highly vulnerable to targeted degradation of HER2 and EGFR. Degradation of HER2 and EGFR induced by PEPD^G278D causes extensive inhibition of oncogenic signaling in trastuzumab-resistant HER2-positive BC cells. This is accompanied by strong growth inhibition of cultured cells, orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of trastuzumab-resistant HER2-positive BC. siRNA knockdown indicates that eliminating both HER2 and EGFR is necessary to maximize therapeutic outcome.</p></div><div><h3>Conclusions</h3><p>This study unravels the therapeutic vulnerability of trastuzumab-resistant HER2-positive BC and shows that an agent that targets the degradation of both HER2 and EGFR is highly effective in overcoming drug resistance in this disease. The findings provide new insights and innovations for advancing treatment of drug-resistant HER2-positive breast cancer that remains an unmet problem.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"74 ","pages":"Article 101078"},"PeriodicalIF":24.3,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000360/pdfft?md5=e537c8dd06677de82f54fb8691471182&pid=1-s2.0-S1368764624000360-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130004","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":"TRIM29 facilitates gemcitabine resistance via MEK/ERK pathway and is modulated by circRPS29/miR-770–5p axis in PDAC","authors":"Wenjie Huang ,&nbsp;Xiaojun Hu ,&nbsp;Xiang He ,&nbsp;Dongyue Pan ,&nbsp;Zhaorong Huang ,&nbsp;Zhanfeng Gu ,&nbsp;Guobing Huang ,&nbsp;Ping Wang ,&nbsp;Chunhui Cui ,&nbsp;Yingfang Fan","doi":"10.1016/j.drup.2024.101079","DOIUrl":"10.1016/j.drup.2024.101079","url":null,"abstract":"<div><h3>Aims</h3><p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Chemotherapy based on gemcitabine (GEM) remains the first-line drug for patients with advanced PDAC. However, GEM resistance impairs its therapeutic effectiveness. Therefore, identifying effective therapeutic targets are urgently needed to overcome GEM resistance.</p></div><div><h3>Methods</h3><p>The clinical significance of Tripartite Motif Containing 29 (TRIM29) was identified by exploring GEO datasets and TCGA database and its potential biological functions were predicted by GSEA analysis. The regulatory axis was established by bioinformatics analysis and validated by mechanical experiments. Then, in vitro and in vivo assays were performed to validate the roles of TRIM29 in PDAC GEM resistance.</p></div><div><h3>Results</h3><p>High TRIM29 expression was associated with poor prognosis of PDAC and functional experiments demonstrated that TRIM29 promoted GEM resistance in PDAC GEM-resistant (GR) cells. Furthermore, we revealed that circRPS29 promoted TRIM29 expression via competitive interaction with miR-770–5p and then activated MEK/ERK signaling pathway. Additionally, both in vitro and in vivo functional experiments demonstrated that circRPS29/miR-770–5p/TRIM29 axis promoted PDAC GEM resistance via activating MEK/ERK signaling pathway.</p></div><div><h3>Conclusion</h3><p>Our results identify the significance of the signaling axis, circRPS29/miR-770–5p/TRIM29-MEK/ERK, in PDAC GEM resistance, which will provide novel therapeutic targets for PDAC treatment.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"74 ","pages":"Article 101079"},"PeriodicalIF":24.3,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130011","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":"A novel SIK2 inhibitor SIC-19 exhibits synthetic lethality with PARP inhibitors in ovarian cancer","authors":"Fang Wang ,&nbsp;Xuejiao Yu ,&nbsp;Jun Qian ,&nbsp;Yumin Cao ,&nbsp;Shunli Dong ,&nbsp;Shenghua Zhan ,&nbsp;Zhen Lu ,&nbsp;Robert C. Bast Jr. ,&nbsp;Qingxia Song ,&nbsp;Youguo Chen ,&nbsp;Yi Zhang ,&nbsp;Jinhua Zhou","doi":"10.1016/j.drup.2024.101077","DOIUrl":"10.1016/j.drup.2024.101077","url":null,"abstract":"<div><h3>Purpose</h3><p>Ovarian cancer patients with HR proficiency (HRP) have had limited benefits from PARP inhibitor treatment, highlighting the need for improved therapeutic strategies. In this study, we developed a novel SIK2 inhibitor, SIC-19, and investigated its potential to enhance the sensitivity and expand the clinical utility of PARP inhibitors in ovarian cancer.</p></div><div><h3>Methods</h3><p>The SIK2 protein was modeled using a Molecular Operating Environment (MOE), and the most favorable model was selected based on a GBVI/WSA dG scoring function. The Chembridge Compound Library was screened, and the top 20 candidate compounds were tested for their interaction with SIK2 and downstream substrates, AKT-pS473 and MYLK-pS343. SIC-19 emerged as the most promising drug candidate and was further evaluated using multiple assays.</p></div><div><h3>Results</h3><p>SIC-19 exhibited selective and potent inhibition of SIK2, leading to its degradation through the ubiquitination pathway. The IC50 of SIC-19 correlated inversely with endogenous SIK2 expression in ovarian cancer cell lines. Treatment with SIC-19 significantly inhibited cancer cell growth and sensitized cells to PARP inhibitors in vitro, as well as in ovarian cancer organoids and xenograft models. Mechanistically, SIK2 knockdown and SIC-19 treatment reduced RAD50 phosphorylation at Ser635, prevented nuclear translocation of RAD50, disrupted nuclear filament assembly, and impaired DNA homologous recombination repair, ultimately inducing apoptosis. These findings highlight the crucial role of SIK2 in the DNA HR repair pathway and demonstrate the significant PARP inhibitor sensitization achieved by SIC-19 in ovarian cancer.</p></div><div><h3>Conclusions</h3><p>SIC-19, a novel SIK2 inhibitor, effectively inhibits tumor cell growth in ovarian cancer by interfering with RAD50-mediated DNA HR repair. Furthermore, SIC-19 enhances the efficacy of PARP inhibitors, providing a promising therapeutic strategy to improve outcomes for ovarian cancer patients.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"74 ","pages":"Article 101077"},"PeriodicalIF":24.3,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764624000359/pdfft?md5=3ded3af8f90b410c4ce7fadd0299ea30&pid=1-s2.0-S1368764624000359-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140053606","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":"Solving the antibacterial resistance in Europe: The multipronged approach of the COST Action CA21145 EURESTOP","authors":"Carole Seguin-Devaux ,&nbsp;Tomislav Mestrovic ,&nbsp;Jacobus J. Arts ,&nbsp;Didem Sen Karaman ,&nbsp;Cristina Nativi ,&nbsp;Dana Reichmann ,&nbsp;Priyanka Sahariah ,&nbsp;Younes Smani ,&nbsp;Patricia Rijo ,&nbsp;Mattia Mori ,&nbsp;on behalf of the COST Action CA21145 EURESTOP","doi":"10.1016/j.drup.2024.101069","DOIUrl":"10.1016/j.drup.2024.101069","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"74 ","pages":"Article 101069"},"PeriodicalIF":24.3,"publicationDate":"2024-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139916201","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":"Development and evaluation of a human CD47/HER2 bispecific antibody for Trastuzumab-resistant breast cancer immunotherapy","authors":"Binglei Zhang ,&nbsp;Jianxiang Shi ,&nbsp;Xiaojing Shi ,&nbsp;Xiaolu Xu ,&nbsp;Le Gao ,&nbsp;Song Li ,&nbsp;Mengmeng Liu ,&nbsp;Mengya Gao ,&nbsp;Shuiling Jin ,&nbsp;Jian Zhou ,&nbsp;Dandan Fan ,&nbsp;Fang Wang ,&nbsp;Zhenyu Ji ,&nbsp;Zhilei Bian ,&nbsp;Yongping Song ,&nbsp;Wenzhi Tian ,&nbsp;Yichao Zheng ,&nbsp;Linping Xu ,&nbsp;Wei Li","doi":"10.1016/j.drup.2024.101068","DOIUrl":"10.1016/j.drup.2024.101068","url":null,"abstract":"<div><p>The treatment for trastuzumab-resistant breast cancer (BC) remains a challenge in clinical settings. It was known that CD47 is preferentially upregulated in HER2⁺ BC cells, which is correlated with drug resistance to trastuzumab. Here, we developed a novel anti-CD47/HER2 bispecific antibody (BsAb) against trastuzumab-resistant BC, named IMM2902. IMM2902 demonstrated high binding affinity, blocking activity, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and internalization degradation effects against both trastuzumab-sensitive and trastuzumab-resistant BC cells <em>in vitro.</em> The <em>in vivo</em> experimental data indicated that IMM2902 was more effective than their respective controls in inhibiting tumor growth in a trastuzumab-sensitive BT474 mouse model, a trastuzumab-resistant HCC1954 mouse model, two trastuzumab-resistant patient-derived xenograft (PDX) mouse models and a cord blood (CB)-humanized HCC1954 mouse model. Through spatial transcriptome assays, multiplex immunofluorescence (mIFC) and <em>in vitro</em> assays, our findings provided evidence that IMM2902 effectively stimulates macrophages to generate C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, thereby facilitating the recruitment of T cells and NK cells to the tumor site. Moreover, IMM2902 demonstrated a high safety profile regarding anemia and non-specific cytokines release. Collectively, our results highlighted a novel therapeutic approach for the treatment of HER2⁺ BCs and this approach exhibits significant anti-tumor efficacy without causing off-target toxicity in trastuzumab-resistant BC cells.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"74 ","pages":"Article 101068"},"PeriodicalIF":24.3,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139830333","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":"AI in infectious diseases: The role of datasets","authors":"Cesar de la Fuente-Nunez","doi":"10.1016/j.drup.2024.101067","DOIUrl":"10.1016/j.drup.2024.101067","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"73 ","pages":"Article 101067"},"PeriodicalIF":24.3,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139884634","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":"ABCB1-dependent collateral sensitivity of multidrug-resistant colorectal cancer cells to the survivin inhibitor MX106-4C","authors":"Zi-Ning Lei ,&nbsp;Najah Albadari ,&nbsp;Qiu-Xu Teng ,&nbsp;Hadiar Rahman ,&nbsp;Jing-Quan Wang ,&nbsp;Zhongzhi Wu ,&nbsp;Dejian Ma ,&nbsp;Suresh V. Ambudkar ,&nbsp;John N.D. Wurpel ,&nbsp;Yihang Pan ,&nbsp;Wei Li ,&nbsp;Zhe-Sheng Chen","doi":"10.1016/j.drup.2024.101065","DOIUrl":"https://doi.org/10.1016/j.drup.2024.101065","url":null,"abstract":"<div><h3>Aims</h3><p>To investigate the collateral sensitivity (CS) of ABCB1-positive multidrug resistant (MDR) colorectal cancer cells to the survivin inhibitor MX106–4C and the mechanism.</p></div><div><h3>Methods</h3><p>Biochemical assays (MTT, ATPase, drug accumulation/efflux, Western blot, RT-qPCR, immunofluorescence, flow cytometry) and bioinformatic analyses (mRNA-sequencing, reversed-phase protein array) were performed to investigate the hypersensitivity of ABCB1 overexpressing colorectal cancer cells to MX106–4C and the mechanisms. Synergism assay, long-term selection, and 3D tumor spheroid test were used to evaluate the anti-cancer efficacy of MX106–4C.</p></div><div><h3>Results</h3><p>MX106–4C selectively killed ABCB1-positive colorectal cancer cells, which could be reversed by an ABCB1 inhibitor, knockout of ABCB1, or loss-of-function ABCB1 mutation, indicating an ABCB1 expression and function-dependent mechanism. MX106–4C's selective toxicity was associated with cell cycle arrest and apoptosis through ABCB1-dependent survivin inhibition and activation on caspases-3/7 as well as modulation on p21-CDK4/6-pRb pathway. MX106–4C had good selectivity against ABCB1-positive colorectal cancer cells and retained this in multicellular tumor spheroids. In addition, MX106–4C could exert a synergistic anti-cancer effect with doxorubicin or re-sensitize ABCB1-positive cancer cells to doxorubicin by reducing ABCB1 expression in the cell population via long-term exposure.</p></div><div><h3>Conclusions</h3><p>MX106–4C selectively kills ABCB1-positive MDR colorectal cancer cells via a novel ABCB1-dependent survivin inhibition mechanism, providing a clue for designing CS compound as an alternative strategy to overcome ABCB1-mediated colorectal cancer MDR.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"73 ","pages":"Article 101065"},"PeriodicalIF":24.3,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139743913","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":"Tumor-acquired somatic mutation affects conformation to abolish ABCG2-mediated drug resistance","authors":"Tomoka Gose ,&nbsp;Ali Rasouli ,&nbsp;Sepehr Dehghani-Ghahnaviyeh ,&nbsp;Po-Chao Wen ,&nbsp;Yao Wang ,&nbsp;John Lynch ,&nbsp;Yu Fukuda ,&nbsp;Talha Shafi ,&nbsp;Robert C. Ford ,&nbsp;Emad Tajkhorshid ,&nbsp;John D. Schuetz","doi":"10.1016/j.drup.2024.101066","DOIUrl":"10.1016/j.drup.2024.101066","url":null,"abstract":"<div><p>ABCG2 is an important ATP-binding cassette transporter impacting the absorption and distribution of over 200 chemical toxins and drugs. ABCG2 also reduces the cellular accumulation of diverse chemotherapeutic agents. Acquired somatic mutations in the phylogenetically conserved amino acids of ABCG2 might provide unique insights into its molecular mechanisms of transport. Here, we identify a tumor-derived somatic mutation (Q393K) that occurs in a highly conserved amino acid across mammalian species. This ABCG2 mutant seems incapable of providing ABCG2-mediated drug resistance. This was perplexing because it is localized properly and retained interaction with substrates and nucleotides. Using a conformationally sensitive antibody, we show that this mutant appears “locked” in a non-functional conformation. Structural modeling and molecular dynamics simulations based on ABCG2 cryo-EM structures suggested that the Q393K interacts with the E446 to create a strong salt bridge. The salt bridge is proposed to stabilize the inward-facing conformation, resulting in an impaired transporter that lacks the flexibility to readily change conformation, thereby disrupting the necessary communication between substrate binding and transport.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"73 ","pages":"Article 101066"},"PeriodicalIF":24.3,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139934065","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":"Fibroblast growth factor receptor 1 inhibition suppresses pancreatic cancer chemoresistance and chemotherapy-driven aggressiveness","authors":"Qingxiang Lin ,&nbsp;Andrea Serratore ,&nbsp;Jin Niu ,&nbsp;Shichen Shen ,&nbsp;Tista Roy Chaudhuri ,&nbsp;Wen Wee Ma ,&nbsp;Jun Qu ,&nbsp;Eugene S. Kandel ,&nbsp;Robert M. Straubinger","doi":"10.1016/j.drup.2024.101064","DOIUrl":"10.1016/j.drup.2024.101064","url":null,"abstract":"<div><h3>Aims</h3><p>Pancreatic ductal adenocarcinoma (PDAC) is often intrinsically-resistant to standard-of-care chemotherapies such as gemcitabine. Acquired gemcitabine resistance (GemR) can arise from treatment of initially-sensitive tumors, and chemotherapy can increase tumor aggressiveness. We investigated the molecular mechanisms of chemoresistance and chemotherapy-driven tumor aggressiveness, which are understood incompletely.</p></div><div><h3>Methods</h3><p>Differential proteomic analysis was employed to investigate chemotherapy-driven chemoresistance drivers and responses of PDAC cells and patient-derived tumor xenografts (PDX) having different chemosensitivities. We also investigated the prognostic value of FGFR1 expression in the efficacy of selective pan-FGFR inhibitor (FGFRi)-gemcitabine combinations.</p></div><div><h3>Results</h3><p>Quantitative proteomic analysis of a highly-GemR cell line revealed fibroblast growth factor receptor 1 (FGFR1) as the highest-expressed receptor tyrosine kinase. FGFR1 knockdown or FGFRi co-treatment enhanced gemcitabine efficacy and decreased GemR marker expression, implicating FGFR1 in augmentation of GemR. FGFRi treatment reduced PDX tumor progression and prolonged survival significantly, even in highly-resistant tumors in which neither single-agent showed efficacy. Gemcitabine exacerbated aggressiveness of highly-GemR tumors, based upon proliferation and metastatic markers. Combining FGFRi with gemcitabine or gemcitabine+nab-paclitaxel reversed tumor aggressiveness and progression, and prolonged survival significantly. In multiple PDAC PDXs, FGFR1 expression correlated with intrinsic tumor gemcitabine sensitivity.</p></div><div><h3>Conclusion</h3><p>FGFR1 drives chemoresistance and tumor aggressiveness, which FGFRi can reverse.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"73 ","pages":"Article 101064"},"PeriodicalIF":24.3,"publicationDate":"2024-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139878453","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}