Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Disrupting MED8-dependent epigenetic reprogramming augments avapritinib sensitivity in PDGFRA-driven glioma.","authors":"Han Xie, Zhang Xiong, Ruixiang Huang, Yongfei Dong, Yunlong Wang, Tao Chen, Chunlong Zhong, Yuan Jiang, Dasheng Tian, Erbao Bian","doi":"10.1186/s13046-026-03736-0","DOIUrl":"10.1186/s13046-026-03736-0","url":null,"abstract":"<p><strong>Background: </strong>PDGFRA genetic alterations are a well-established oncogenic driver in gliomas. However, targeted monotherapy against PDGFRA such as avapritinib has achieved limited clinical efficacy, and the mechanism underlying avapritinib resistance remains poorly understood.</p><p><strong>Methods: </strong>Multi-omics analysis of clinical samples identified super-enhancer (SE) complex components. Comprehensive preclinical evaluation was performed using glioma cell lines, glioma stem cells, patient-derived cells, xenografts, and organoids. Mechanistic investigations integrated Cleavage Under Targets and Tagmentation, chromatin immunoprecipitation, co-immunoprecipitation, mass spectrometry, protein fragment complementation, and dual-luciferase reporter assays.</p><p><strong>Results: </strong>Functional and clinical analyses identified the SE complex component MED8 as significantly upregulated in gliomas and correlated with poor prognosis. MED8 was essential for tumor proliferation and survival both in vitro and in vivo. Mechanistically, MED8 cooperated with CDK7 to bind and activate the SEs of PDGFRA, sustaining high transcriptional output of this oncogene. We repurposed FDA-approved venetoclax as a first-in-class MED8-targeting agent that potently sensitizes to avapritinib, exerting synergistic effects in multiple preclinical models.</p><p><strong>Conclusions: </strong>This study delineates a novel MED8-SE-PDGFRA epigenetic axis driving resistance. The combination of avapritinib and venetoclax, co-targeting the oncogenic signal and its transcriptional regulator, presents a translatable dual-targeting strategy to improve outcomes in PDGFRA-driven glioma.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13360484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976627","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":"DDX5 (p68) and UbE2T as emerging superior cancer therapeutic targets: dual molecular glue target degradation by FL118 for conquering difficult-to-treat cancers.","authors":"Fengzhi Li, Xiang Ling, Sayan Chakraborty, Dean G Tang, Karen McLean, Wenjie Wu, Norbert Sule, Deepak Vadehra, Christos Fountzilas, Ajay Gupta, Clare Twist, Joyce Ohm, Gurkamal Chatta, Scott I Abrams","doi":"10.1186/s13046-026-03733-3","DOIUrl":"10.1186/s13046-026-03733-3","url":null,"abstract":"<p><p>Growing evidence has revealed that DEAD-box RNA helicase 5 (DDX5, also known as p68) and ubiquitin-conjugating enzyme E2T (UbE2T) are two emerging and highly promising cancer therapeutic targets. This article provides the first comprehensive review of the physical and functional relationship between these two cancer targets, further refining their therapeutic potentials in solid cancers. In addition, the consequences of simultaneously degrading DDX5 and UbE2T proteins by the small-molecule dual molecular glue degrader FL118 in difficult-to-treat advanced cancers are presented.Specifically, this article reviews: (1) the roles of DDX5 and UbE2T in diverse cancer DNA repair pathways; (2) the physical binding relationship and potential functional roles of DDX5 in topoisomerase regulation; (3) the involvement of DDX5 in EZH2- and NANOG-associated prostate cancer stem cell (PCSC)-driven neuroendocrine prostate cancer (NEPC), castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC); (4) the contributions of DDX5 and UbE2T to inflammatory and immune regulation within the tumor microenvironment (TME); (5) FL118 as a small-molecule dual molecular glue degrader selectively targeting both DDX5 and UbE2T; (6) the high efficacy of FL118 against multiple difficult-to-treat advanced and metastatic cancers, including advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), osteosarcoma, Ewing sarcoma, ovarian cancer, and glioma/glioblastoma; (7) the resistance of ABCG2-expressing cancer cells to common anticancer agents but not to FL118; (8) the favorable pharmacokinetic and toxicology profiles of FL118 in mice, rats, and dogs; (9) the distinct functions of DDX5 in normal tissues, cells, and organs versus cancer; and (10) FL118 as a drug platform enabling the development of novel analogs and derivatives.Based on this review, we conclude that DDX5 and UbE2T represent superior anticancer therapeutic targets, and that the high efficacy of FL118 against multiple difficult-to-treat cancers is attributable to its function as a bona fide small-molecule dual molecular glue degrader that physically targets and degrades both DDX5 and UbE2T. Strikingly, this activity is observed regardless of the expression status of ABC transporter proteins, ABCG2/BCRP, ABCB1/Pgp/MDR1, and/or ABCC1/MRP1 in cancer cells.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976361","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":"Superior anti-DLBCL efficacy of novel organic arsenical Z2-A-Z2 through ROS-mediated apoptosis and critical NF-κB/IκBα signaling pathway inhibition.","authors":"Wenjiao Wei, Yanni Ma, Yujiao Liu, Xian Zhang, Shuangnian Xu, Qingfeng Li, Dongdong Zhang","doi":"10.1186/s13046-026-03724-4","DOIUrl":"10.1186/s13046-026-03724-4","url":null,"abstract":"<p><strong>Objective: </strong>Diffuse large B-cell lymphoma (DLBCL) often resists therapy due to aberrant activation of NF-κB signaling pathway. We synthesized and evaluated Z2-A-Z2, a novel organic arsenical, hypothesized to target this survival pathway, aiming to assess its efficacy and mechanism against DLBCL.</p><p><strong>Materials and methods: </strong>The novel compound Z2-A-Z2 was synthesized and verified by ¹H CMR, ¹³C CMR, and high-resolution mass spectrometry. Its anti-proliferative activity was assessed in GCB- and ABC-subtype DLBCL cell lines and normal peripheral blood mononuclear cells (PBMCs) using CCK-8 assays. Mechanisms were elucidated through flow cytometry (apoptosis, ROS, ΔΨm), Western blot (apoptotic and NF-κB pathway proteins), and enzyme activity assays. The causal role of ROS was confirmed by N-Acetylcysteine rescue (NAC) experiments, and the criticality of NF-κB inhibition was validated using p65 overexpression and pharmacological inhibition. Efficacy and safety were ultimately verified in SU-DHL-6 and U2932 xenograft model.</p><p><strong>Results: </strong>Z2-A-Z2 demonstrated potent and selective anti-proliferative activity against DLBCL cell lines, achieving an average IC₅₀ of approximately 1.1 µM. This efficacy was 3- to 6-fold superior to arsenic trioxide (ATO), while exhibiting minimal cytotoxicity toward normal PBMCs and B cells. Mechanistically, Z2-A-Z2 induced profound mitochondrial-mediated apoptosis and G2/M cell cycle arrest through a unique dual action of simultaneously triggering catastrophic oxidative stress and critically suppressing the pro-survival NF-κB/IκBα signaling axis. Further investigation revealed a bidirectional regulation where ROS acts upstream to suppress p65 activity, while p65 in turn modulates drug-induced ROS generation. In vivo studies further validated these findings, showing that Z2-A-Z2 resulted in a robust suppression of tumor growth in a xenograft model, accompanied by diminished NF-κB/IκBα activity and increased apoptosis, alongside an excellent safety profile.</p><p><strong>Conclusion: </strong>Z2-A-Z2 is a promising organic arsenical with superior efficacy and safety over ATO. Its unique dual-action strategy of simultaneously inducing oxidative stress and critically inhibiting the NF-κB/IκBα signaling axis, positioning it as a strong clinical candidate for effectively treating DLBCL.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976679","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":"ASCL2-mediated macrophage-myofibroblast transition generates immunosuppressive CAF_7 in NSCLC bone metastases.","authors":"Jinfeng Wang, Jin Qian, Xiujia Yang, Chongquan Huang, Tiantian Wei, Jielong Zhou, Guoqing Zhong, Zhenhai Zhang, Yu Zhang","doi":"10.1186/s13046-026-03735-1","DOIUrl":"10.1186/s13046-026-03735-1","url":null,"abstract":"<p><strong>Background: </strong>NSCLC frequently metastasizes to bone, where the microenvironment becomes immunosuppressive, limiting immunotherapy efficacy. Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) contribute to immune evasion, but CAF subset origins and roles in bone metastases remain unclear. We investigated whether TAMs undergo macrophage-to-myofibroblast transition (MMT) to generate an immunosuppressive CAF subpopulation in bone lesions, driven by ASCL2.</p><p><strong>Methods: </strong>We integrated single-cell RNA sequencing of primary lung tumors and bone metastases with pseudotime and regulon analyses to resolve CAF heterogeneity and nominate MMT regulators. Findings were validated by immunofluorescence and flow cytometry in patient tissues and a murine bone-metastasis model. In vitro, TGF-β1-induced MMT with ASCL2 knockdown/rescue and T-cell co-culture assays were used to assess CAF_7-like induction and immunosuppressive function. In vivo, macrophage depletion/reconstitution, donor and endogenous tracing, and macrophage-directed ASCL2 or Il6ra knockdown were performed in a mouse bone-metastasis model to assess CAF_7-like abundance, tumor burden, and T-cell states; ASCL2 inhibition was further evaluated with PD-1 blockade for tumor control and survival.</p><p><strong>Results: </strong>Seven CAF subsets were identified, including a bone metastasis-enriched subset (CAF_7) that co-expressed macrophage, MHC-II, and stromal markers. Trajectory analyses, together with the observation that LLC-conditioned medium induced a CAF_7-like shift in bone marrow-derived macrophages in vitro and that both exogenous GFP-labeled BMDMs and endogenous macrophage-lineage-traced cells acquired CAF_7-like features in the bone metastatic microenvironment, supported TAM-to-CAF_7-like transition via MMT. CAF_7 accumulation correlated with increased Treg infiltration, CD8⁺ T cell exhaustion, and poorer survival. Regulon analysis highlighted ASCL2 as a CAF_7-associated regulator; ASCL2 increased in vitro during MMT, and in vivo ASCL2 protein and ASCL2⁺ CAF_7-like cells were enriched in bone-metastasis lesions versus sham marrow or subcutaneous tumors. ASCL2 knockdown in macrophages blocked MMT, reducing CAF_7-like cells and associated Treg and exhausted CD8⁺ T cells, and suppressing tumor growth. Mechanistically, ASCL2 directly transactivated Il6ra, and macrophage Il6ra knockdown phenocopied ASCL2 silencing in vivo. Notably, ASCL2 silencing synergized with anti-PD-1 therapy, improving tumor control and extending survival.</p><p><strong>Conclusions: </strong>In NSCLC bone metastases, ASCL2-driven MMT converts TAMs into immunosuppressive CAF_7 that promotes immune escape. Targeting ASCL2 disrupts this transition, restores anti-tumor immunity, and may improve immunotherapy efficacy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13325787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976145","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":"Tie2 inhibition disrupts TMEM doorway function and reduces dissemination in pancreatic ductal adenocarcinoma.","authors":"Erika Pereira Zambalde, Lina A Ariyan, Francisco Puerta-Martinez, Yu Qin Zhu, Priyanka Patil, Nicole C Panarelli, Jiufeng Li, Yookyung Jung, Christian Adkisson, Jakeb Petersen, Dianne Cox, Hava Gil-Henn, Robert Eddy, Ben Z Stanger, David Entenberg, Maja H Oktay, John S Condeelis, John C McAuliffe","doi":"10.1186/s13046-026-03730-6","DOIUrl":"10.1186/s13046-026-03730-6","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy with limited treatment options. Metastatic dissemination is the principal cause of mortality in PDAC, yet the cellular mechanism by which PDAC tumor cells enter the bloodstream remains unknown. A portal of intravasation is the Tumor Microenvironment of Metastasis (TMEM) doorways. The TMEM doorway is composed of a tumor cell, a Tie2 + macrophage, and endothelial cell, in direct contact triggering a brief, localized vascular opening that permits intravasation.</p><p><strong>Methods: </strong>We performed time-lapse intravital microscopy in PDAC mouse models to visualize serum extravasation and tumor cell intravasation. TMEM doorway density was quantified using immunohistochemistry of resected human PDAC specimes. TMEM doorway activity was quantified by aligned immunohistochemistry/immunofluorescence of tumor specimens. Mechanistic underpinnings of intravasation were tested using an in vitro intravasation transendothelial migration (iTEM) assay. Tie2 signaling was inhibited in vivo with the Tie2 inhibitor rebastinib (~ 0.44 mg/day in chow for 3 weeks). A macrophage-specific Tie2 conditional knockout mouse was generated to evaluate macrophage Tie2-mediated PDAC dissemination. The therapeutic impact of Tie2 blockade was evaluated in an orthotopic perioperative PDAC model incorporating distal pancreatectomy and perioperative FOLFIRINOX plus rebastinib. Statistical analyses used included Mann-Whitney and Kruskal-Wallis tests for clinicopathologic comparisons, one-way ANOVA with Tukey's post hoc test for iTEM, Student's t-test for two-group comparisons, and Kaplan-Meier survival analysis with log-rank testing.</p><p><strong>Results: </strong>In vivo imaging revealed transient, localized vascular openings spatially linked to TMEM doorways. PDAC tumor cell intravasation was observed at TMEM doorways. TMEM doorways were detectable in human PDAC tissues; higher TMEM density was associated with aggressive pathologic factors and was reduced after neoadjuvant therapy. Tie2 inhibition selectively impaired macrophage-driven vascular opening and reduced TMEM doorway activity, diminished tumor cell transendothelial migration, and lowered disseminated tumor cell burden in vivo. In therapeutic studies, Tie2 inhibition combined with FOLFIRINOX improved survival compared with FOLFIRINOX alone.</p><p><strong>Conclusions: </strong>Intravasation and dissemination is TMEM doorway mediated in PDAC. TMEM doorway function is mediated by Tie2 signaling. Inhibition of Tie2 pharmacologically and genetically decreases TMEM doorway function and PDAC dissemination. Tie2 inhibition may have therapeutic potential combined with chemotherapy or emerging therapies for PDAC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13196212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960512","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":"Retraction Note: LncRNA CCAT1 facilitates the progression of gastric cancer via PTBP1-mediated glycolysis enhancement.","authors":"Cong Zhang, Huixia Wang, Qingwei Liu, Suli Dai, Guo Tian, Xintong Wei, Xiaoya Li, Lianmei Zhao, Baoen Shan","doi":"10.1186/s13046-026-03737-z","DOIUrl":"10.1186/s13046-026-03737-z","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13179620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147950297","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":"cGAS-STING pathway regulated by spatiotemporal heterogeneity of tumor microenvironment and precision therapy strategies in lung cancer.","authors":"Jing-Ying Ye, Ying Pan, Miao Li, Fang-Qing Shen, Fu-Lu Ren, Hao-Yu Wang, Ming Li, Yun Wang","doi":"10.1186/s13046-026-03738-y","DOIUrl":"10.1186/s13046-026-03738-y","url":null,"abstract":"<p><p>The cGAS-STING pathway is a central regulator of innate immunity and exhibits a complex dual function in lung cancer: it can activate anti-tumor immune responses but also promote immune escape and metastasis. This \"double-edged sword\" effect is highly dependent on the spatiotemporal heterogeneity of the tumor microenvironment (TME), referring to dynamic changes in immune and metabolic features across different regions and disease stages. To optimize existing therapies, overcome resistance, and develop novel treatments to improve patient outcomes, it is crucial to deeply understand the interaction between the TME and the cGAS-STING pathway. This review systematically discusses the pro-tumor and anti-tumor mechanisms of the cGAS-STING pathway in lung cancer; the modulation of cGAS-STING pathway activity by TME spatiotemporal heterogeneity, via the dynamic interplay of distinct cell types and physicochemical gradients; and cGAS-STING-driven precision immunotherapy and artificial intelligence (AI) optimization. Integrating TME spatiotemporal heterogeneity, immunometabolism crosstalk, with cGAS-STING pathway function may provide new insights for improving therapeutic strategies, reversing resistance, and enhancing survival outcomes for lung cancer patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13339432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960382","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":"Co-targeting CDK4/6 and MEK reverses mesenchymal transition in therapy-refractory BRAF-altered pediatric high-grade glioma.","authors":"Lisa Mayr, Leah Mager, Lisa Gabler-Pamer, Dominik Kirchhofer, Julia Freund, Kallen Schwark, Benison Lau, Sarah Machreich, Daniel Senfter, Mia Neumüller, Alexandra Lang, Sibylle Madlener, Anna Laemmerer, Katharina Bruckner, Carola N Jaunecker, Bernhard Robl, Romina Walter, Julia Schueler, Andreas Peyrl, Amedeo A Azizi, Christian Dorfer, Karl Roessler, Sabine Spiegl-Kreinecker, Christine Haberler, Aniello Federico, Apurva Gopisetty, Gudrun Schleiermacher, Stefan M Pfister, Birgit Geoerger, Louis Chesler, Gilles Vassal, Marcel Kool, Leonhard Müllauer, Carl Koschmann, Walter Berger, Johannes Gojo, Daniela Lötsch","doi":"10.1186/s13046-026-03725-3","DOIUrl":"10.1186/s13046-026-03725-3","url":null,"abstract":"<p><strong>Background: </strong>BRAF-altered pediatric high-grade gliomas (pHGG) harbor a dismal prognosis. Although targeted therapy with BRAF and MEK inhibitors provides initial benefit, resistance emerges rapidly in clinical practice indicating an urgent need for improved therapeutic strategies. As BRAF mutations frequently co-occur with homozygous CDKN2A/B loss, we investigated CDK4/6 inhibition as a rational therapeutic strategy.</p><p><strong>Methods: </strong>Using BRAF-mutant cell and human-to-organoid transplant (HOT) models, we assessed the impact of CDK4/6 and MEK inhibitors as mono- or combination therapies on viability, apoptosis, senescence, and molecular signaling. Activation of signaling pathways in primary and recurrent matched samples pre- and post-combined MEK and BRAF treatment was examined by RNA sequencing. In vivo efficacy was evaluated in orthotopic and subcutaneous patient-derived xenograft (PDX) models, as well as in one clinical case.</p><p><strong>Results: </strong>BRAF-mutant, CDKN2A/B-deficient pHGGs displayed strong sensitivity to the CDK4/6 inhibitor abemaciclib in addition to the MEK inhibitor trametinib. These tumors were particularly vulnerable to combined abemaciclib and trametinib treatment, which induced senescence and apoptosis, and uniquely suppressed mTOR activity. Both HOT and PDX models exhibited tumor regression, prolonged survival and sustained response even after therapy discontinuation. These effects were accompanied by a decreased mesenchymal-like cellular phenotype, as indicated by lower CD44 expression and a shift toward a more rounded cell morphology. Interestingly, trametinib- and dabrafenib post-treatment samples exhibited further increase in CD44 levels, along with upregulation of PI3K and hypoxia signaling, indicating therapy-associated reinforcement of mesenchymal transition. The combination of trametinib and ribociclib was translated into clinical application, by showing good response of a patient with BRAF-altered and therapy-refractory pHGG.</p><p><strong>Conclusion: </strong>Our study demonstrated enhanced and prolonged effects of combined CDK4/6 and MEK inhibition in BRAF/CDKN2A-co-altered recurrent pHGG. We further provide evidence that the aggressive mesenchymal cell compartment is particularly targeted by this treatment combination, warranting further preclinical and clinical investigation.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960450","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":"CtBP promoted P4HB mediates SLC7A11 maturation to confer ferroptosis resistance in triple-negative breast cancer.","authors":"Lifen Wang, Hongxia Xu, Tianyu Liu, Dongliang Zhu, Liping Chen, Tzu-Ming Liu, Shuhai Lin, Xueyi Liu, Hao Feng, Li Wang, Li-Jun Di","doi":"10.1186/s13046-026-03727-1","DOIUrl":"10.1186/s13046-026-03727-1","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is characterized by aggressive clinical behaviour and frequent resistance to chemotherapy. While ferroptosis-an iron-dependent form of cell death driven by lipid peroxidation-holds promise as a therapeutic strategy, its efficacy is often limited by adaptive resistance mechanisms that remain incompletely understood. C-terminal binding protein (CtBP) is an oncogene associated with poor prognosis in TNBC; however, whether CtBP confers resistance to oxidative stress and ferroptosis, thereby contributing to its oncogenic function, remains unknown.</p><p><strong>Methods: </strong>We utilized both in vitro cell lines and in vivo mouse models to investigate the role of CtBP in regulating oxidative stress and ferroptosis sensitivity. Integrative analyses, including transcriptomics, metabolomics, and clinical data interrogation, were employed to elucidate the mechanisms underlying CtBP-mediated resistance. Key mechanistic findings were further validated in clinical TNBC specimens using protein correlation analysis.</p><p><strong>Results: </strong>We identified CtBP as a stress-inducible gene that is essential for ferroptosis resistance in TNBC. Mechanistically, CtBP promotes resistance by transcriptionally upregulating Prolyl 4-Hydroxylase Subunit Beta (P4HB). P4HB, localized to the endoplasmic reticulum (ER), functions as a chaperone to facilitate the correct folding and membrane maturation of SLC7A11, the catalytic subunit of the system xc^-  cystine/glutamate antiporter pivotal for glutathione (GSH) biosynthesis. We demonstrated that P4HB-mediated SLC7A11 maturation relies on its disulfide isomerase activity and ER retention signal (KDEL). Depletion of either CtBP or P4HB impaired SLC7A11 membrane trafficking, lead to accumulation of lipid peroxides and sensitization to ferroptosis. Conversely, P4HB overexpression restored SLC7A11 function and ferroptosis resistance in CtBP-deficient cells. Furthermore, significant positive correlations among CtBP, P4HB, and SLC7A11 expressions in clinical samples underscore the critical role of CtBP/P4HB/SLC7A11 axis in driving cancer aggressiveness. In vivo, targeting the CtBP/P4HB/SLC7A11 axis sensitized TNBC xenografts to the ferroptosis inducer RSL3, significantly suppressing tumor growth and lung metastasis.</p><p><strong>Conclusions: </strong>This study identifies the CtBP/P4HB/SLC7A11 axis as a critical mediator of ferroptosis resistance in TNBC. These findings highlight this pathway as a potent therapeutic target to overcome resistance and enhance the efficacy of ferroptosis-inducing regimens in TNBC treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960396","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":"Bi-directional regulation between NAD/NAMPT and IFN-γ/PD-L1 axes via BRD4/IRF1 and mitochondrial respiration in metastatic cutaneous melanoma.","authors":"Irene Fiorilla, Beatrice Ghezzi, Alessia Ponzano, Enrico Moiso, Federica Riccardo, Nicoletta Tommasi, Lidia Avalle, Giovanna Carrà, Filippo Ugolini, Edoardo Calussi, Alberto Maria Todesco, Sabrina Digiovanni, Filippo Casone, Giulia Rizza, Luca Ponzone, Anna Szumera-Ciećkiewicz, Maria Cavaletto, Paolo Ettore Porporato, Laura Conti, Chiara Riganti, Daniela Massi, Enzo Calautti, Valentina Audrito","doi":"10.1186/s13046-026-03734-2","DOIUrl":"10.1186/s13046-026-03734-2","url":null,"abstract":"<p><strong>Background: </strong>Metastatic cutaneous melanoma (MCM) is primarily treated with BRAF/MEK inhibitors and immune checkpoint inhibitors (ICIs), but the long-term efficacy of these therapies is often limited by acquired resistance. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD biosynthesis, is frequently upregulated in MCM, supporting metabolic rewiring and targeted therapy resistance. Interferon-γ (IFN-γ) signaling plays a central role in melanoma biology, exerting both antitumor and immunoregulatory effects, linked with the onset of therapeutic resistance. Emerging evidence suggests that metabolic pathways may critically modulate IFN-γ responses; however, the functional interplay between NAD/NAMPT metabolism and IFN-γ signaling in melanoma cells remains poorly defined.</p><p><strong>Methods: </strong>We integrated transcriptomic, bioinformatic, biochemical, and functional approaches in human and murine melanoma cell lines, together with analyses of TCGA datasets and a tissue microarray (TMA) cohort. Mechanistic studies included pharmacological and genetic perturbation of Bromodomain and Extra-Terminal motif (BET) epigenetic factor BRD4, Interferon Regulatory Factor 1 (IRF1), and NAMPT, chromatin immunoprecipitation (ChIP) assays, and metabolic analyses. Tumor-T cell co-culture systems were used to assess the impact of melanoma-cell NAMPT modulation on T-cell behavior.</p><p><strong>Results: </strong>IFN-γ induced NAMPT expression through a BRD4/IRF1-dependent transcriptional program. In turn, NAMPT activity was required to sustain IFN-γ signaling, as its inhibition impaired STAT1 activation and downstream transcriptional responses. Mechanistically, NAMPT-dependent NAD metabolism supported mitochondrial complex I activity and oxidative metabolism and was required for efficient BRD4 recruitment to IFN-responsive promoters, including CD274/PD-L1 and NAMPT itself. Across melanoma datasets and patient samples, NAMPT expression correlated with IFN-γ-responsive genes, including PD-L1. Functionally, modulation of NAMPT in melanoma cells influenced T-cell cytotoxicity and migration in co-culture systems.</p><p><strong>Conclusions: </strong>Overall, these findings identify NAMPT as a key metabolic component of the IFN-γ response network in melanoma cells, establishing a feed-forward regulatory circuit linking cytokine signaling, chromatin regulation, and mitochondrial metabolism. This work provides a framework to investigate how metabolic control of IFN-γ signaling shapes tumor-immune interactions.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13326467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147943663","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}