Journal of Experimental & Clinical Cancer Research最新文献

{"title":"CDK4-selective inhibitor AU2-94 for the treatment of advanced and therapy-resistant prostate cancer.","authors":"Ava Safaroghli-Azar, Travis Croft, Laychiluh B Mekonnen, Jimma Lenjisa, Maja Dickel, Raj K Shrestha, Samyukta Sita, Nicholas Choo, Michael Roach, Sunita K C Basnet, Mitchell G Lawrence, Luke A Selth, Shudong Wang","doi":"10.1186/s13046-026-03763-x","DOIUrl":"10.1186/s13046-026-03763-x","url":null,"abstract":"<p><strong>Introduction: </strong>CDK4-selective inhibitors are emerging as promising anticancer agents. Relative to dual CDK4/6 inhibitors, CDK4-selective inhibitors have the potential to retain efficacy while improving tolerability. However, the therapeutic value and mechanistic consequences of selectively targeting CDK4 in prostate cancer remain largely undefined. Here, we investigated the anti-tumour activity and mode of action of the CDK4 inhibitors AU2-94 and atirmociclib across diverse prostate cancer models.</p><p><strong>Methods: </strong>Antiproliferative activity was assessed in a panel of AR-driven and AR-independent prostate cancer cell lines spanning hormone-sensitive and castration-resistant states. Efficacy was further evaluated in organoids derived from patient-derived xenografts and in xenograft mouse models. Biochemical and molecular analyses were performed to evaluate CDK4 selectivity, RB pathway engagement, transcriptional reprogramming, and downstream effects on cell-cycle regulation, and resistance-associated programmes. AU2-94 was also tested in combination with standard-of-care therapies (enzalutamide and docetaxel) and the PI3K inhibitor alpelisib.</p><p><strong>Results: </strong>AU2-94 exhibited greater selectivity for CDK4 compared with atirmociclib. AU2-94 suppressed proliferation across prostate cancer models irrespective of AR status and retained activity in aggressive and therapy-resistant settings. In RB-proficient in vitro models, AU2-94 reduced RB phosphorylation, attenuated E2F1-dependent transcriptional outputs, activated AR signalling, and decreased expression of proliferation-associated factors such as FOXM1. In vivo, AU2-94 inhibited the growth of both AR-driven (LNCaP) and AR-independent (PC3) xenografts and suppressed RB pathway signalling. Moreover, AU2-94 demonstrated additive or synergistic effects when combined with enzalutamide, docetaxel, or alpelisib that were associated with reinforced cell-cycle blockade and suppression of resistance-associated signalling.</p><p><strong>Conclusion: </strong>These findings establish selective CDK4 inhibition as a therapeutically active and mechanistically rational strategy in prostate cancer and support AU2-94 as a candidate for further preclinical and clinical development, including in combination regimens for advanced and therapy-resistant disease.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148273689","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":"Targeting the lipid desaturation network in cancer: from metabolic plasticity to precision therapeutics.","authors":"Justyna J Gleba, John A Copland, Han W Tun","doi":"10.1186/s13046-026-03747-x","DOIUrl":"10.1186/s13046-026-03747-x","url":null,"abstract":"<p><p>Lipid desaturation is a fundamental biochemical process essential for maintaining membrane fluidity, energy storage, and cellular signaling. It is increasingly recognized that this homeostatic network is frequently dysregulated by malignant cells to support proliferation, evade programmed cell death, and facilitate immune evasion. There are two primary lipid desaturation pathways: the conversion of saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs) by stearoyl-CoA desaturase 1 (SCD1), and the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) via the fatty acid desaturases (FADS). This review explores how tumors utilize the SCD1 axis to mitigate lipotoxic endoplasmic reticulum (ER) stress and ferroptosis. Furthermore, we discuss how the FADS axis presents a distinct metabolic paradox: while it promotes oncogenic signaling and structural plasticity, it concurrently creates an actionable vulnerability to ferroptosis by enriching membranes with peroxidation-prone PUFAs. This metabolic rewiring provides a strong biological rationale for precision therapeutics.We trace the clinical development of desaturase inhibitors, highlighting the recent entry of SCD1 inhibitor, MTI-301, in a Phase 1 clinical trial for solid tumors and the potential repurposing of Aramchol, while detailing how FADS2 plasticity (the \"sapienic shunt\") drives therapeutic resistance. By integrating these insights into desaturation lipidomics, metabolic modulation via diet-drug interactions, synergistic combination regimens, and stimuli-responsive nanomedicine, we highlight the translational potential of targeting lipid desaturation to overcome metabolic plasticity and treatment resistance in aggressive malignancies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148266930","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":"ZEB1 integrates stemness, differentiation blockade and immune suppression to orchestrate osteosarcoma aggressiveness.","authors":"Anna Zaccaria, Caterina Cascini, Chiara Ratti, Laura Botti, Davide Pernici, Valeria Cancila, Elisabetta Armiraglio, Antonina Parafioriti, Cristina Meazza, Sabina Sangaletti, Claudio Tripodo, Katia Scotlandi, Mario P Colombo, Daniele Lecis, Claudia Chiodoni","doi":"10.1186/s13046-026-03757-9","DOIUrl":"10.1186/s13046-026-03757-9","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma (OS) is a highly aggressive bone malignancy primarily affecting children and adolescents, with limited therapeutic options. The transcription factor ZEB1, a key regulator of epithelial-mesenchymal transition (EMT), promotes cancer stemness and tumor progression.</p><p><strong>Methods: </strong>We investigated ZEB1 role in OS using genetic knockout and silencing in murine and patient-derived cellular OS models. Using in vitro functional assays, we assessed the effect of ZEB1 down-modulation on stemness (sarcosphere formation), anchorage-independent growth, chemotherapy sensitivity, and osteoblastic differentiation (osteogenic markers and matrix mineralization), while gene expression profiling provided hints on ZEB1 regulation of tumor cell transcriptional program. In vivo studies evaluated tumor growth and lung metastasis in ZEB1-deficient models, while ZEB1 restoration experiments mechanistically proved its role in OS aggressiveness.</p><p><strong>Results: </strong>ZEB1 loss in OS mouse models markedly reduced stemness-associated gene expression and functional sarcosphere formation, impaired anchorage-independent growth, and increased sensitivity to chemotherapy. Furthermore, ZEB1 inhibition restored osteoblastic differentiation capacity, evidenced by upregulation of osteogenic markers and matrix mineralization. In vivo, ZEB1 deletion in mouse OS cells significantly hindered tumor growth and lung metastasis, accompanied by increased tumor differentiation and decreased infiltration of pro-tumoral macrophages. Gene expression profiling revealed suppression of oncogenic pathways and inflammatory mediators upon ZEB1 loss, while restoration of ZEB1 rescued OS aggressive phenotype.</p><p><strong>Conclusions: </strong>Overall, our findings position ZEB1 as a critical driver of OS aggressiveness by regulating stemness, cellular differentiation, oncogenic signaling, and immune infiltration, and highlight differentiation-based therapeutic strategies as a promising avenue for osteosarcoma treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148260217","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":"Inhibition of 5'-tiRNA^Gly restores anti-PD-1 immunotherapy efficacy via DLST-mediated OGDHL succinylation in gastric cancer.","authors":"Xinliang Gu, Yu Zhang, Yang Li, Xun Li, Yuening Sun, Shuo Ma, Xinyue Qin, Yuejiao Huang, Xianjuan Shen, Ming Zheng, Quanhua Yi, Zhiyuan Tang, Shaoqing Ju","doi":"10.1186/s13046-026-03758-8","DOIUrl":"10.1186/s13046-026-03758-8","url":null,"abstract":"<p><strong>Background: </strong>Transfer RNA-derived small RNAs (tsRNAs) have been implicated in tumor progression and immune regulation in recent years. However, the specific role of tRNA halves (tiRNAs), a subclass of tsRNAs, in modulating immunotherapy response remains unexplored.</p><p><strong>Methods and results: </strong>In this study, 5'-tiRNA^Gly levels were examined in gastric cancer (GC) patients and found to be upregulated, especially in non-responders to anti-PD-1 therapy. Elevated 5'-tiRNA^Gly levels were also associated with diminished oxoglutarate dehydrogenase-like (OGDHL) expression. Further exploration revealed that 5'-tiRNA^Gly bound to DLST and promoted OGDHL destabilization, whereas targeted inhibition of 5'-tiRNA^Gly restored OGDHL stability through succinylation at lysine 910, enhanced tricarboxylic acid (TCA) cycle activity, and reduced glutamine-derived metabolic reprogramming. Additionally, 5'-tiRNA^Gly was found to decrease the activity of α-ketoglutarate dehydrogenase and inhibit succinylation of histone H3 at lysine 79 (H3K79suc), thereby downregulating PD-L1 transcription and reducing therapeutic responsiveness to PD-1 inhibitors. Conversely, restoration of this epigenetic modification upon 5'-tiRNA^Gly inhibition facilitated PD-L1 transcription, thereby sensitizing tumors to anti-PD-1 therapy.</p><p><strong>Conclusion: </strong>Our findings indicate that targeting 5'-tiRNA^Gly may represent a promising strategy to enhance responsiveness to anti-PD-1 therapy in GC patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13681928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148240501","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":"Glycolytic cancer-associated fibroblasts orchestrate metabolic remodeling in the tumor microenvironment.","authors":"Xinyu Cui, Akshaya Poonepalle, Chloe Shay, Yong Teng","doi":"10.1186/s13046-026-03756-w","DOIUrl":"10.1186/s13046-026-03756-w","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment and are predominantly classified according to transcriptional identity. However, this framework overlooks an important dimension of CAF biology, metabolic heterogeneity, which remains insufficiently characterized and is not incorporated into current classification systems. In this review, we advance the concept of glycolytic cancer-associated fibroblasts (glyCAFs) as a metabolically defined stromal subset that functions as a central organizer of the tumor ecosystem. Integrating insights from metabolic profiling, transcriptomics, spatial analyses, and emerging therapeutic studies, we outline a model in which glyCAFs coordinate tumor progression through three interconnected mechanisms: metabolic support of oxidative tumor cells via lactate shuttling, suppression of antitumor immunity through extracellular acidification, and spatial organization of the invasive niche through structured stromal barriers. We further discuss evidence from solid tumors supporting the broader relevance of glyCAF-driven metabolic coupling as a conserved feature of tumor biology. Importantly, we highlight targetable vulnerabilities within the glyCAF-tumor axis, including pathways currently under clinical investigation, and consider the potential of glyCAF abundance as a biomarker of therapeutic response, particularly to immune checkpoint blockade. By integrating metabolic state as an orthogonal axis of CAF identity, we suggest a revised framework for tumor stratification and highlight new opportunities to disrupt tumor-stroma co-dependencies through metabolic-immunologic combination therapies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148220317","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":"Intracellular lipid droplets positively regulate the dormancy of colorectal cancer cells depending on ELF1-ACSL5 signaling.","authors":"Wancheng Liao, Rui Yin, Fan Zuo, Yangkun Li, Jiao Deng, Yanqi Li, Xiaolan Li, Deding Tao, Xuelai Luo, Weike Ji, Jichao Qin","doi":"10.1186/s13046-026-03754-y","DOIUrl":"10.1186/s13046-026-03754-y","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer recurrence is largely attributed to dormant tumor cells that evade therapy. The role of organelle metabolism, particularly lipid droplets (LDs) accumulation, in maintaining tumor dormancy remains poorly understood. This study aimed to investigate how LDs contribute to dormancy and to identify key regulatory mechanisms.</p><p><strong>Methods: </strong>Using patient-derived xenograft models and colorectal cancer cell lines, we established chemotherapy-induced dormant, proliferative, and recurrent cells. Transcriptomic profiling identified key regulatory genes and lipidomics of LDs was performed by Liquid Chromatography‑Tandem Mass Spectrometry. Functional validation was performed via genetic knockdown/overexpression, pharmacological inhibition, and mutational analysis. Lipid droplet content, reactive oxygen species levels, and dormancy markers were assessed using staining, flow cytometry, and immunoblotting. Clinical correlation was evaluated using patient datasets and survival analysis.</p><p><strong>Results: </strong>Dormant cells exhibited elevated LD levels compared to proliferative or recurrent cells. Transcriptomic analysis identified ACSL5 as a key upregulated gene in dormant cells. ACSL5 promoted LD accumulation, which in turn reduced intracellular reactive oxygen species and stabilized dormancy by sequestering oxidized lipids. The transcription factor ELF1 directly bound the ACSL5 promoter, establishing the ELF1-ACSL5 regulatory axis. Disruption of this axis depleted LDs, increased ROS, and forced dormant cells to exit dormancy. Clinically, high ACSL5 expression correlated with poor prognosis in colorectal cancer patients.</p><p><strong>Conclusion: </strong>This study defines a novel ELF1-ACSL5-lipid droplet axis that maintains colorectal cancer dormancy by promoting lipid sequestration and redox homeostasis. These findings reveal organelle-centric metabolic reprogramming as a fundamental dormancy mechanism and nominate this axis as a promising therapeutic target to prevent cancer recurrence.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148229061","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":"Loss of CSE couples with BRAF V600E to fuel thyroid cancer metastatic progression through zinc-dependent activation of the EMT machinery.","authors":"Shichen Xu, Huixin Yu, Hongxun Wu, Zongfu Pan, Jiajie Xu, Yun Zhu, Botao Huang, Gangming Cai, Xiaobo Gu, Min Yang, Donghui Pan, Jie Pan, Jing Wu, Xian Cheng, Jiandong Bao, Li Zhang","doi":"10.1186/s13046-026-03752-0","DOIUrl":"10.1186/s13046-026-03752-0","url":null,"abstract":"<p><strong>Background: </strong>BRAF V600E, the principal oncogenic driver in papillary thyroid carcinoma (PTC), strongly correlated with lymph node metastasis, yet the underlying molecular mechanisms remain elusive.</p><p><strong>Methods: </strong>This study screened effector related to the BRAF V600E mutation and PTC progression through bioinformatics analysis. The precise functional roles and regulatory networks of cystathionine γ-lyase (CSE), a primary hydrogen sulfide (H₂S)-producing enzyme, in thyroid cancer metastasis were then investigated in cell and mice models. Finally, these findings were further validated in a cohort of clinical pathological samples.</p><p><strong>Results: </strong>We identified that CSE is aberrantly silenced in advanced thyroid cancer. Mechanistically, BRAF V600E-driven MAPK activation upregulates miR-31-5p, which directly targets the CSE 3'UTR to inhibit its translation. The consequent H₂S deficiency disrupts intracellular metallo-homeostasis, triggering intracellular zinc accumulation that stabilizes Zeb1, MMP-2, thereby orchestrating the epithelial-mesenchymal transition (EMT). Critically, the metastatic potential of thyroid cancer cells relies strictly on CSE enzymatic activity. Pharmacological reconstitution of the H₂S pool using exogenous donors effectively bypasses CSE enzymatic deficiency, eliminates excess zinc, and reactivates metastasis-suppressive signaling.</p><p><strong>Conclusions: </strong>These findings uncover a novel miR-31-5p/CSE/H₂S/Zinc axis that fuels BRAF-driven progression. These findings provide a compelling mechanistic rationale for utilizing H₂S-based interventions as a potential therapeutic strategy against BRAF-driven thyroid cancer metastasis.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13474713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213190","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":"Alkylating agents activate an SLFN11-dependent vulnerability that confers PARP-1 inhibitor sensitivity in kidney cancer.","authors":"Chenliang Wang, Ming Zhu, Lei Bao, Vanina Toffessi Tcheuyap, James Brugarolas, Weibo Luo, Yingfei Wang","doi":"10.1186/s13046-026-03743-1","DOIUrl":"10.1186/s13046-026-03743-1","url":null,"abstract":"<p><strong>Background: </strong>PARP inhibitors have demonstrated notable clinical benefit, particularly in tumors with BRCA1/2 mutations. Clear cell renal cell carcinoma (ccRCC) carrying wild type (WT) BRCA1/2 is resistant to PARP inhibitor monotherapy. Strategies to enhance the sensitivity of BRCA1/2-WT ccRCC to PARP inhibitors remain challenging.</p><p><strong>Methods: </strong>An in vitro chemical screen was performed to identify alkylating agents that synergize with PARP inhibition using cell viability assays. ccRCC sensitivity to individual alkylating agents was further assessed by measuring PARP-1 activity. The therapeutic effects of monotherapy and combination treatment with alkylating agents and PARP inhibitors were evaluated through DNA damage repair assays, cell viability assays, colony formation assays, ccRCC cell xenograft assays, and ccRCC patient-derived xenograft assays. Mechanistic insights and DNA repair pathway involvement were assessed using comparative expression profiling and gain- and loss-of-function approaches.</p><p><strong>Results: </strong>BRCA1/2-WT ccRCC exhibits markedly higher PARP-1 activity compared to breast cancers. A subset of alkylating agents, including Temozolomide (TMZ) and Streptozocin, is identified to induce hyperactivation of PARP-1, creating a PARP-1 dependency in ccRCC cells that renders these cells sensitive to PARP inhibitors in vitro and in mice. Mechanistically, SLFN11 is selectively upregulated and boosts proteasomal degradation of BRCA1 protein in ccRCC cells. Loss of SLFN11 increases BRCA1 levels and enhances homologous recombination repair, mitigating prolonged excessive DNA damage in ccRCC cells following combination treatment with TMZ and Olaparib. SLFN11 is inversely correlated with BRCA1 expression and potentiates the therapeutic efficacy of TMZ and Olaparib combination treatment in ccRCC patient-derived xenograft models.</p><p><strong>Conclusion: </strong>Our findings reveal an intrinsic SLFN11-dependent vulnerability in ccRCC that synergizes with alkylating agents to induce an acquired PARP-1 dependency, thereby sensitizing BRCA1/2-WT tumors to PARP inhibition. Therefore, this work uncovers a potential therapeutic strategy for targeting SLFN11-high kidney cancers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13471403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148206788","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":"Pharmacologic reprogramming of virus-tumor crosstalk enhances measles virus antitumor activity in BRAF mutant colorectal cancer models.","authors":"Valery Chavez, Melissa Montero, Ngoc Huong Giang Tran, Carolina Merchan Mendes, Yuguang Ban, Rimpi Khurana, Michelle Ceccarelli, Jaime R Merchan","doi":"10.1186/s13046-026-03749-9","DOIUrl":"10.1186/s13046-026-03749-9","url":null,"abstract":"<p><strong>Background: </strong>Oncolytic viruses are promising cancer biotherapies but often show limited durability as single agents due to tumor-intrinsic resistance mechanisms. Because therapeutic efficacy is shaped by dynamic virus-tumor-stromal interactions, pharmacologic strategies that reprogram this interface may enhance virotherapy responses. Here, we investigate whether targeting tumor stress and survival pathways with triptolide and its prodrug Minnelide can enhance the oncolytic efficacy of measles virus in colorectal cancer.</p><p><strong>Methods: </strong>The in vitro effects of CD46 targeted (MV-GFP) and dual targeted (MV-CD46-muPA) oncolytic MV, alone and with Triptolide were assessed in human CRC cell lines. Mechanistic studies included gene expression analysis, functional proteomics, and western blotting. In vivo efficacy of MV-CD46-muPA combined with Minnelide was evaluated in HT29 and HCT116 xenografts. Biological effects were further characterized using transcriptomic profiling (RNA-seq), targeted gene expression (NanoString), and histological analysis.</p><p><strong>Results: </strong>Triptolide enhanced MV mediated oncolysis in vitro, particularly in BRAF V600E mutant CRC cell lines, and modulated key cancer pathways including AKT, apoptosis and metabolism. In vivo, Minnelide significantly improved the efficacy of systemically administered MV-CD46-muPA in human CRC xenografts, with greater effects in BRAF mutant (HT29) models. The combination modulated cell cycle, metabolism, and survival associated genes, promoted apoptosis, and improved intratumoral viral distribution. These molecular effects resulted in reduced tumor cell proliferation (Ki67), decreased angiogenesis (CD31), and increased apoptosis (TUNEL) relative to single agents.</p><p><strong>Conclusion: </strong>Triptolide and Minnelide significantly enhance the oncolytic efficacy of measles virus in colorectal cancer, particularly in BRAF-mutant tumors in vivo, through reprogramming of virus-tumor-stromal interactions. This reprogramming arises from coordinated modulation of survival, metabolic, and stromal signaling pathways and is accompanied by improved intratumoral viral distribution. These findings position virus-tumor-stromal crosstalk as a central mechanistic axis of virotherapy response and provide a strong rationale for the translational and clinical development of rational virus-drug combination strategies in colorectal cancer and other malignancies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148195138","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":"SERPINE2-mediated activation of JAK2/STAT3 facilitates NRF2 nuclear translocation and GCLC transcription to confer ferroptosis resistance and lenvatinib resistance in hepatocellular carcinoma.","authors":"Kan Liu, Shenglan Huang, Yongkang Xu, Ye Mao, Ning Chen, Yixin Yuan, Qinwen Xiao, Shumin Fu, Jianbing Wu","doi":"10.1186/s13046-026-03746-y","DOIUrl":"10.1186/s13046-026-03746-y","url":null,"abstract":"<p><strong>Background: </strong>Acquired resistance remains a major obstacle in molecular-targeted therapy for advanced hepatocellular carcinoma (HCC). This study aimed to elucidate the role and underlying mechanisms of SERPINE2 in mediating lenvatinib resistance by suppressing ferroptosis.</p><p><strong>Methods: </strong>We analyzed SERPINE2 expression and its clinical prognostic relevance using public databases (TCGA) and clinical samples (tumor tissues and serum) from patients with HCC treated with lenvatinib. By establishing hypoxic and acquired lenvatinib-resistant HCC cell models, combined with subcutaneous xenograft and orthotopic liver cancer mouse models, we systematically evaluated the functional role of SERPINE2 in tumor proliferation, apoptosis, ferroptosis, and lenvatinib resistance in vitro and in vivo. Mechanistic insights were obtained through transcriptome sequencing (RNA-seq), quantitative proteomics, co-immunoprecipitation (Co-IP), nuclear-cytoplasmic fractionation, and measurement of key ferroptosis indicators (lipid ROS, mitochondrial membrane potential, and transmission electron microscopy). Finally, we assessed the therapeutic potential of targeted interventions combining a JAK inhibitor (Ruxolitinib) or NRF2 inhibitor (ML385) with lenvatinib to overcome resistance in vitro and in vivo.</p><p><strong>Results: </strong>SERPINE2 was markedly upregulated in hypoxic and lenvatinib-resistant HCC models and clinical tissues, correlating with a poor prognosis. Mechanistically, SERPINE2 activates the JAK2/STAT3 signaling pathway, promotes the STAT3-NRF2 interaction, and facilitates NRF2 nuclear translocation. This upregulates the antioxidant enzyme GCLC, which strengthens glutathione synthesis, inhibits lipid peroxidation and ferroptosis, and ultimately confers lenvatinib resistance. Inhibiting SERPINE2, STAT3, or GCLC restored ferroptosis and re-sensitized HCC cells to lenvatinib. Furthermore, the combination treatments exhibited significant synergistic antitumor effects in vitro and in vivo. Clinically, elevated SERPINE2 levels positively correlated with GCLC, predicted worse survival outcomes, and effectively distinguished lenvatinib-resistant patients.</p><p><strong>Conclusions: </strong>This study established the SERPINE2-JAK2/STAT3-NRF2-GCLC signaling axis as a key mechanism driving ferroptosis resistance and lenvatinib treatment failure. Targeting this axis provides a novel therapeutic strategy for overcoming lenvatinib resistance in HCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148195130","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}