Cancer letters最新文献

{"title":"Auranofin facilitates gemcitabine sensitivity by regulating TXNRD1-related ferroptosis in pancreatic ductal adenocarcinoma","authors":"Si-Yuan Lu ,&nbsp;De-Liang Fang ,&nbsp;Zi-Yi Zhao ,&nbsp;Ying-Qin Zhu,&nbsp;Zhi-De Liu,&nbsp;Ming-Jian Ma,&nbsp;Jing-Yuan Ye,&nbsp;Qiong-Cong Xu,&nbsp;Xiao-Yu Yin","doi":"10.1016/j.canlet.2025.218058","DOIUrl":"10.1016/j.canlet.2025.218058","url":null,"abstract":"<div><div>Gemcitabine-based combination chemotherapy remains the first-line treatment for pancreatic ductal adenocarcinoma (PDAC). However, numerous patients with PDAC develop resistance to gemcitabine, highlighting the need to identify sensitizers or resistance targets. In this study, we constructed a patient-derived xenograft (PDX) model using resected PDAC tissue from patients and established stable gemcitabine-resistant and -sensitive PDX models. RNA sequencing analysis of the gemcitabine-resistant PDX model and cell lines revealed that altered iron ion metabolism significantly affected gemcitabine resistance in PDAC. Gemcitabine-resistant cell lines exhibited altered iron ion levels, which contributed to decreasing lipid peroxidation and ferroptosis. To identify biomarkers of gemcitabine resistance, we established PDX-based machine learning features and found that they may differentiate the effectiveness of chemotherapy and immunotherapy in different patients. TXNRD1 was identified as a potential oncogene that promotes cell migration and proliferation, while inhibiting cell apoptosis. Mechanistically, TXNRD1 knockdown restricted P65 expression and phosphorylation, leading to SLC7A11 depletion and enhanced ferroptosis. This activated ferroptosis, induced by SLC7A11 inhibition, further suppressed gemcitabine resistance in PDAC. Auranofin, a TXNRD1 inhibitor, induced ferroptosis and exerted synergistic effects with gemcitabine in PDAC therapy. Auranofin additionally enhanced the anticancer effects of gemcitabine in a drug-resistant PDAC PDX model. Collectively, TXNRD1 is a potential target for overcoming gemcitabine resistance. Auranofin can inhibit TXNRD1 activation, thereby sensitizing PDAC cells to gemcitabine. Combination therapy with auranofin and gemcitabine may have translational potential for PDAC chemotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"634 ","pages":"Article 218058"},"PeriodicalIF":10.1,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124338","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":"Hinokitiol preferentially suppresses metastatic lung adenocarcinoma via TMDD1-mediated ferroptosis induction and iron-sulfur cluster inhibition.","authors":"Yanbin Kuang, Suyang Yang, Xiaoting Tian, Huiyan Cheng, Beibei Liu, Congcong Zhang, Baohui Han, Wei Zhang, Xiao Zhang, Yuqing Lou","doi":"10.1016/j.canlet.2025.218046","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.218046","url":null,"abstract":"<p><p>Dysregulated ISC metabolism has been implicated in cancer progression, but its role in LUAD pathogenesis and therapeutic targeting remains poorly understood. Here, we demonstrate that ISC biogenesis is significantly upregulated in LUAD, driven by transcription factors KLF15 and ZNF384, which activate GLRX5, LYRM4, NFS1 and BOLA3 promoters. IL-1β promotes PCAF mitochondrial translocation, releasing EP300 to amplify KLF15/ZNF384-mediated transcriptional activation. The natural monoterpenoid Hinokitiol inhibits LUAD growth by disrupting EP300-KLF15/ZNF384 interactions, suppressing ISC biogenesis gene expression and inducing ferroptosis. Mechanistically, the membrane protein TMDD1, particularly its cytoplasmic domain, promotes Hinokitiol's anti-tumor effects by facilitating EP300-KLF15/ZNF384 dissociation and inhibiting ISC biogenesis. Remarkably, Hinokitiol exhibits stage-dependent efficacy, with superior suppression of metastatic (stage IV) tumors linked to heightened ferroptosis sensitivity. This study not only elucidates the transcriptional machinery governing ISC biogenesis in LUAD but also highlights Hinokitiol's dual mechanism as a promising stage-specific therapeutic agent, offering novel strategies for advanced disease management.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218046"},"PeriodicalIF":10.1,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102650","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 histone lysine methyltransferase NSD3 drives osteosarcomagenesis by inactivating ARID3A","authors":"Jinchang Lu ,&nbsp;Yang Shao ,&nbsp;Sanjay Saw ,&nbsp;Hui Fang ,&nbsp;Guohui Song ,&nbsp;Yan Chen ,&nbsp;Qinglian Tang ,&nbsp;Geoffrey Wood ,&nbsp;Jin Wang ,&nbsp;Paul Waterhouse ,&nbsp;Jingnan Shen ,&nbsp;Rama Khokha","doi":"10.1016/j.canlet.2025.218045","DOIUrl":"10.1016/j.canlet.2025.218045","url":null,"abstract":"<div><div>Osteosarcomas (OS) have highly chaotic genomes, yet their cancer drivers are poorly defined. Leveraging cross-species OS genomics we identify the frequent amplification of NSD3, a histone lysine methyltransferase and expose the NSD3-ARID3A axis as a core pathway in osteosarcomagenesis. Loss- and gain-of-function studies with CRISPR-Cas9 and lentivirus systems establish the causal role of NSD3 in OS tumor growth and spontaneous metastasis. NSD3 specifically enhances H3K27 di-methylation to initiate oncogenic reprogramming and inactivates the transcriptional repressor ARID3A. This culminates in altered expression of instructive genes <em>RUNX2</em>, <em>MMP13</em>, <em>OCT4</em> and <em>NANOG</em> generating a shift in osteosarcoma cell differentiation to a primitive state. In human OS, NSD3 overexpression is seen in patient tumors and predicts a poor clinical outcome. Our study uncovers the crucial epigenetic dysregulation of histone lysine methyltransferase in osteosarcoma, opening new possibilities for therapy with epigenetic drugs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218045"},"PeriodicalIF":10.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085227","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":"Aurora kinase A inhibition as a synthetic lethality strategy in ARID1A-mutated gastroenteropancreatic neuroendocrine carcinoma","authors":"Maria Urbanova ,&nbsp;Fabrice Viol ,&nbsp;Laura Ruiz-Cañas ,&nbsp;Efthymios Koniaris ,&nbsp;Rihards Saksis ,&nbsp;Sandra Batres-Ramos ,&nbsp;Julie Earl ,&nbsp;Agapi Kataki ,&nbsp;Verona Buocikova ,&nbsp;Monika Burikova ,&nbsp;Marina Cihova ,&nbsp;Lucia Rojikova ,&nbsp;Peter Makovicky ,&nbsp;Miroslava Matuskova ,&nbsp;Yvonne Kohl ,&nbsp;Andrea Riedmayer ,&nbsp;Marianna Makova ,&nbsp;Ladislav Baciak ,&nbsp;Daniel Gogola ,&nbsp;Olesja Rogoza ,&nbsp;Joerg Schrader","doi":"10.1016/j.canlet.2025.218033","DOIUrl":"10.1016/j.canlet.2025.218033","url":null,"abstract":"<div><div>Chemotherapy with cisplatin (CDDP) and etoposide (ETO) is the standard treatment for gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). Despite high initial response rates, treatment-related toxicity and acquired resistance remain significant clinical challenges. No molecularly targeted therapies are currently established for this aggressive cancer. Here, we evaluated Aurora kinase inhibition with alisertib (ALI) as a synthetic lethality strategy in ARID1A-deficient GEP-NEC. Subcutaneous and orthotopic xenograft models were established in immunodeficient mice using the GEP-NEC-derived NT-38 cell line, and the therapeutic efficacy of ALI was compared with CDDP + ETO. Tumor responses were assessed by immunohistochemistry, Western blotting, and RNA sequencing. To confirm ARID1A dependency, transient knockdown was induced in the pancreatic neuroendocrine NT-18LM cell line, demonstrating that ALI sensitivity is significantly enhanced in ARID1A-deficient cells. ALI achieved antitumor efficacy comparable to chemotherapy and was well tolerated, with minimal weight loss relative to CDDP + ETO. Distant metastases, an early feature of GEP-NEC, developed in five animals over six weeks, two of which were treated with ALI and three controls. Transcriptomic profiling revealed convergence of both treatments on signal transduction, focal adhesion, receptor tyrosine kinase, and VEGFA-VEGFR2 signaling, while ALI uniquely enriched pathways related to pancreatic secretion, lipid metabolism, protein processing in the endoplasmic reticulum, and extracellular matrix organization. These findings establish Aurora kinase inhibition as mechanistically distinct and selectively effective in ARID1A-deficient GEP-NEC. Given its efficacy, favorable tolerability, and ARID1A-dependent specificity, ALI may represent a promising alternative to platinum-based chemotherapy, offering a strong rationale for further development of mechanism-driven combination strategies for GEP-NEC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"634 ","pages":"Article 218033"},"PeriodicalIF":10.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079725","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":"P2RY8::TSC22D3 is a novel fusion associated with chemoresistance in leukemia by activating PI3K-AKT pathway","authors":"Minyi Cai ,&nbsp;Zhimei Xia ,&nbsp;Chen Shao ,&nbsp;Wenxin Du ,&nbsp;Ji Cao ,&nbsp;Bo Yang ,&nbsp;Qiaojun He ,&nbsp;Xiaojun Xu ,&nbsp;Jingying Zhang ,&nbsp;Xuejing Shao ,&nbsp;Meidan Ying","doi":"10.1016/j.canlet.2025.218040","DOIUrl":"10.1016/j.canlet.2025.218040","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218040"},"PeriodicalIF":10.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085256","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":"Radiosensitization of intrahepatic cholangiocarcinoma and metastatic disease in the liver using microbubble cavitation: results from a phase 2 clinical trial","authors":"Corinne E. Wessner ,&nbsp;Tania Siu Xiao ,&nbsp;Allison Chang ,&nbsp;Jenny Liu ,&nbsp;Weelic Chong ,&nbsp;Ji-Bin Liu ,&nbsp;Kristen Bradigan ,&nbsp;Flemming Forsberg ,&nbsp;Andrej Lyshchik ,&nbsp;Patrick O'Kane ,&nbsp;Scott W. Keith ,&nbsp;Stephen R. Topper ,&nbsp;Kevin Anton ,&nbsp;John R. Eisenbrey","doi":"10.1016/j.canlet.2025.218026","DOIUrl":"10.1016/j.canlet.2025.218026","url":null,"abstract":"<div><div>Ultrasound triggered microbubble destruction (UTMD) has been shown to sensitize tumors to radiation. This study evaluated the feasibility, safety, and efficacy of using UTMD for radiosensitization in participants with intrahepatic cholangiocarcinoma (ICC) and/or metastatic disease to the liver (MDL) receiving Yttrium-90 transarterial radioembolization (Y90-TARE). This was a prospective single-center IRB-approved clinical trial. Participants received four contrast ultrasound sessions: 1–2 weeks prior to Y90-TARE, 1–4 h post-treatment, and 1 week and 2 weeks post-Y90-TARE. The control group consisted of 1:1 nearest-neighbor propensity score matched historical controls participants that received Y90-TARE as part of standard-of-care. Safety was evaluated through general lab values, physiological monitoring and adverse events. Treatment response was determined by a 1–6 month CT/MRI and evaluated using modified Response Evaluation Criteria in Solid Tumors (mRECIST). Final analysis included 15 participants in each group. There were no differences in general lab values between groups (p &gt; 0.15). In study participants, there were no differences in physiological monitoring between pre and post UTMD sessions (p &gt; 0.20). There was a trend toward a better response distribution in the study group compared to the control group (study group: 0 % progressive disease (0/14), 29 % participants with stable disease (4/14), 21 % participants with partial response (3/14), 50 % participants with complete response (7/14) and control group: 33 % participants with progressive disease (5/15), 27 % with stable disease (4/15), 13 % with partial response (2/15), 27 % with complete response (4/15) when evaluating long-term imaging, p = 0.06). The addition of UTMD in participants that received Y90-TARE was feasible, safe, and might deliver improved treatment response.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218026"},"PeriodicalIF":10.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079663","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":"Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications","authors":"Zhe Wang,&nbsp;Ziyan Gu,&nbsp;Wendi Mo,&nbsp;Haijun Zhang","doi":"10.1016/j.canlet.2025.218038","DOIUrl":"10.1016/j.canlet.2025.218038","url":null,"abstract":"<div><div>Immuno-Oncology has transformed cancer therapeutics, yet its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Once considered merely a metabolic byproduct of glycolysis, lactate is now recognized as a critical regulator of immune TME through both direct metabolic effects and its derivative modification, histone lysine lactylation (Kla). Within the TME, lactate and Kla reprogram signaling pathways that impair immune function, thereby facilitating tumor immune escape. This review synthesizes emerging evidence positioning lactate metabolism and histone Kla as pivotal immunosuppressive modulators within the TME. Tumor-derived lactate, produced through the Warburg effect, acidifies the TME and disrupts immune cell function via two interconnected mechanisms: direct metabolic interference and epigenetic reprogramming via Kla. Histone Kla represents a novel post-translational modification that drives immunosuppressive signaling in immune cells, serving as a prognostic biomarker across multiple cancers. Moreover, we highlight therapeutic strategies targeting lactate metabolism, which show considerable promise in overcoming the current limitations of immunotherapy and enhancing its clinical efficacy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218038"},"PeriodicalIF":10.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057416","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":"Polyamines in pancreatic cancer: reshaping the immunosuppressive tumor microenvironment","authors":"Shijuan Jiang ,&nbsp;Bo Ren ,&nbsp;Chen Ding ,&nbsp;Changwei Du,&nbsp;Zhe Cao,&nbsp;Gang Yang,&nbsp;Hua Huang,&nbsp;Taiping Zhang","doi":"10.1016/j.canlet.2025.218016","DOIUrl":"10.1016/j.canlet.2025.218016","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, characterized by its aggressiveness and poor outcomes. Emerging evidence implicates dysregulated polyamine metabolism as a key driver of PDAC immunosuppression, yet the mechanisms underlying this metabolic-immune crosstalk remain poorly defined. This review summarizes recent findings demonstrating that PDAC is uniquely dependent on glutamine-derived ornithine for de novo polyamine synthesis, orchestrated by the <em>KRAS-MYC</em> axis. Through metabolic reprogramming of immune cells, polyamines polarize tumor-associated macrophages toward M2-like phenotypes, expand myeloid-derived suppressor cells, and impair T cell activation. Crucially, the immunomodulatory effects of polyamines are source-dependent: tumor-derived spermidine promotes T cell exhaustion, whereas dietary spermidine enhances antitumor immunity through fatty acid oxidation. Preclinical studies have highlighted that polyamine-targeted therapy, including biosynthesis inhibitors, arginine deprivation agents and polyamine analogue, is a promising strategy to reverse immunosuppression and enhance the efficacy of checkpoint inhibitors. These evidences establish polyamine metabolism as a therapeutic vulnerability in PDAC, offering novel diagnostic tools and combination regimens to overcome therapeutic resistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218016"},"PeriodicalIF":10.1,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058349","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":"Improved identification of tumor-specific TCRs from circulating lymphocytes using autologous colorectal tumor organoids","authors":"Lisha Ma ,&nbsp;Xiya Wang ,&nbsp;Qianjing Zhang ,&nbsp;Zhaoya Gao ,&nbsp;Xiangwen Ji ,&nbsp;Zhilang Li ,&nbsp;Yixian Li ,&nbsp;Pengchong Zhang ,&nbsp;Xuan Che ,&nbsp;Yun Sun ,&nbsp;Yun Bai ,&nbsp;Hongkui Deng","doi":"10.1016/j.canlet.2025.218036","DOIUrl":"10.1016/j.canlet.2025.218036","url":null,"abstract":"<div><div>The identification of effective T cell receptors (TCRs) with specific reactivity against tumor cells is critical for the efficacy of TCR-engineered T cell therapy. However, different approaches for screening effective TCRs remain to be explored. We developed an optimized approach to identify effective TCRs based on an organoid culture system with patient-derived tumor cells in the presence of oxaliplatin and autologous dendritic cells. By coculturing the immunogenic debris of patient tumor cells from the organoid, we successfully enriched tumor-reactive CD4⁺ and CD8⁺ T cells, enhanced the activation and proliferation of T cells, and could facilitate the identification of tumor-reactive CD8⁺ T cells from patients with MHC I-downregulated tumors. We further used autologous tumor organoids to verify that candidate tumor-specific TCRs can elicit patient-specific tumor recognition and killing when expressed in allogeneic T cells. Our organoid-based tumor-reactive T cell enrichment system and TCR screening validation platform provide an empirical strategy for the isolation of tumor-reactive T cells and can advance the study of TCR-engineered T cell therapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218036"},"PeriodicalIF":10.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045191","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":"NNMT-driven metabolic reprogramming creates a NAMPT druggable vulnerability and reveals liquid biopsy biomarkers for TKI resistance in EGFR-mutant NSCLC","authors":"I. Pulido ,&nbsp;J.C. García-Cañaveras ,&nbsp;M.L. Rodríguez ,&nbsp;J.H. Becker ,&nbsp;A. López ,&nbsp;M. Aupí ,&nbsp;S. Aparisi ,&nbsp;L. Chuliá-Peris ,&nbsp;E. Tamayo-Torres ,&nbsp;C. Carreres-Rey ,&nbsp;J. Alcácer Fernández-Coronado ,&nbsp;M. Benet ,&nbsp;S. Montero ,&nbsp;S. Mena ,&nbsp;J. Sandoval ,&nbsp;J. Pereda ,&nbsp;J. Alcácer ,&nbsp;S. Calabuig-Fariñas ,&nbsp;E. Jantus-Lewintre ,&nbsp;A. Cremades ,&nbsp;J. Carretero","doi":"10.1016/j.canlet.2025.218032","DOIUrl":"10.1016/j.canlet.2025.218032","url":null,"abstract":"<div><div>Lung cancer is the deadliest neoplasia worldwide. Despite the availability of targeted therapies like tyrosine kinase inhibitors (TKIs) for <em>EGFR</em>-driven tumours in Non-Small Cell Lung Cancer (NSCLC), drug resistance remains a major factor that dramatically cuts life expectancy. Here we identify how increased expression of nicotinamide N-methyltransferase (NNMT) in TKI-resistant cancer cells diverts nicotinamide to synthesise 1-Methylnicotinamide (1-MNA) and lowers NAD⁺ levels that generates a druggable nicotinamide phosphoribosyltransferase (NAMPT) metabolic vulnerability. We also report that high blood levels of 1-MNA, the by-product of NNMT activity, are significantly associated with lower survival rates in EGFR TKI-treated NSCLC patients. Taken together, our findings describe a new and highly specific non-genetic metabolic synthetic lethality for mesenchymal-like tumours, which exposes NAMPT as an <em>in vivo</em> druggable target and establishes 1-MNA as a novel liquid biopsy biomarker to predict and monitor EGFR TKI resistance in NSCLC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218032"},"PeriodicalIF":10.1,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039211","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}