Cancer researchPub Date : 2026-10-06DOI: 10.1158/0008-5472.can-25-3126
Laura Leonhardt,Jia Mei,Audrey M. Hendley,Suhail A. Ansari,Sudipta Ashe,David I. Berrios,Lars-Henrik Joost,Lina Fadel,Merve Yigin,Johannes Wirth,Nadja Lewandowski-Hoppe,Hasna Maachi,Felix Schicktanz,Marianne Remke,Richard Lindner,Lucia Y. Li,Oghenekevwe M. Gbenedio,Yuehan Hui,Elie Ghabi,Claudio Luchini,Giuseppe Malleo,Jin He,Rondell P. Graham,Jeroen P. Roose,David W. Dawson,N Henriette. Uhlenhaut,Annette Feuchtinger,Katja Steiger,Grace E. Kim,Matthias Hebrok
{"title":"KDM6 Histone Demethylases Tune Pancreatic Cancer Plasticity","authors":"Laura Leonhardt,Jia Mei,Audrey M. Hendley,Suhail A. Ansari,Sudipta Ashe,David I. Berrios,Lars-Henrik Joost,Lina Fadel,Merve Yigin,Johannes Wirth,Nadja Lewandowski-Hoppe,Hasna Maachi,Felix Schicktanz,Marianne Remke,Richard Lindner,Lucia Y. Li,Oghenekevwe M. Gbenedio,Yuehan Hui,Elie Ghabi,Claudio Luchini,Giuseppe Malleo,Jin He,Rondell P. Graham,Jeroen P. Roose,David W. Dawson,N Henriette. Uhlenhaut,Annette Feuchtinger,Katja Steiger,Grace E. Kim,Matthias Hebrok","doi":"10.1158/0008-5472.can-25-3126","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-3126","url":null,"abstract":"Abstract Aberrant epigenetic regulation is a central driver of tumorigenesis, and the reversibility of epigenetic modifications underscores their potential as therapeutic targets. Epigenetic factors often function in a highly context-dependent manner, necessitating rigorous study of their dynamic and complex roles. Here, we uncovered an intricate regulation of tumor development and plasticity by the KDM6 family of H3K27me3 histone demethylases in pancreatic ductal adenocarcinoma (PDAC), a disease with sustained high mortality and limited treatment options. Temporally resolving KRAS-driven tumor development revealed a switch from tumor suppressive to oncogenic functions for KDM6B, with implications for tumor aggressiveness in rodents and patients. These oncogenic functions were mediated by regulation of NOTCH signaling, a pathway known to promote PDAC tumorigenesis. Concurrent elimination of KDM6A and KDM6B led to profound phenotypic changes resembling sarcomatoid carcinomas, a rare, poorly characterized subtype of human PDAC. These tumors exhibited altered oncogenic networks, including NOTCH and JNK signaling, that may support development of therapies tailored to molecular subtypes. Given the critical and distinct activities of KDM6 histone demethylases during PDAC development, targeting KDM6 activities may be beneficial in the right cellular and temporal context.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092261","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}
Cancer researchPub Date : 2026-10-05DOI: 10.1158/0008-5472.can-25-5176
Adarsha P. Malla, Matthew Flick, Jennifer R. Fang, Xiaoxuan Fan, Chixiang Chen, Angad Beniwal, Chris Sereduk, Richard Drexler, Alexandros Poulopoulos, Michelle Monje, Pavlos Anastasiadis, Nhan L. Tran, Jeffrey A. Winkles, Graeme F. Woodworth
{"title":"Longitudinal Surgical Modeling of Early Glioblastoma Recurrence Reveals Emergence of Margin-Associated Neural Programs","authors":"Adarsha P. Malla, Matthew Flick, Jennifer R. Fang, Xiaoxuan Fan, Chixiang Chen, Angad Beniwal, Chris Sereduk, Richard Drexler, Alexandros Poulopoulos, Michelle Monje, Pavlos Anastasiadis, Nhan L. Tran, Jeffrey A. Winkles, Graeme F. Woodworth","doi":"10.1158/0008-5472.can-25-5176","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-5176","url":null,"abstract":"Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086752","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":"Targeting SLC38A5 Overcomes αPD-1 Immunotherapy Resistance by Alleviating Glutamine Competition Between Glioblastoma Cells and T Cells","authors":"Zhuohao Liu,Jiani Lin,Tao Chen,Weimin Zhang,Ran Ye,Ying-Gui Yang,Na Li,Jiayi Zhou,Guisen Tan,Chenci Wang,Zhengwei Wang,Xiaoping Wu,Kenneth King-yip Cheng,Jie Mao,Ming Gao,Jiacheng Liu,Xiaojuan Pei,Chi-Fai Ng,Yuliang Wang,Dinglan Wu","doi":"10.1158/0008-5472.can-26-0774","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0774","url":null,"abstract":"Abstract Despite the clinical success of programmed cell death protein 1 (PD-1) checkpoint blockade in many cancer types, its efficacy in glioblastoma remains notably limited, underscoring the critical need to uncover primary resistance mechanisms and identify synergistic therapeutic targets. To discover genes modulating αPD-1 immunotherapy response, we performed an in vivo CRISPR-Cas9 screen in immunocompetent mice bearing glioblastoma, which prioritized the glutamine (Gln) transporter SLC38A5 as a candidate modulator of αPD-1 immunotherapy efficacy. In human glioblastoma, SLC38A5 was significantly upregulated compared with normal brain tissue. Ablation of SLC38A5 did not impair glioblastoma cell intrinsic growth but profoundly sensitized glioblastoma to αPD-1 therapy in a CD8+ T cell-dependent manner, leading to enhanced anti-tumor immunity and tumor control. Mechanistically, SLC38A5 deficiency created a Gln-enriched tumor microenvironment by impairing Gln uptake of glioblastoma cells. This metabolic rewiring enhanced CD8+ T cell function via SLC1A5-dependent Gln utilization and promoted MHC-I-mediated antigen presentation in glioblastoma cells through a Gln-glutathione (GSH)-reactive oxygen species (ROS) axis. Furthermore, an SLC38A5-targeting nanobody was developed that efficiently accumulated in orthotopic glioblastoma and potentiated αPD-1 therapy to suppress brain tumor growth in vivo. Overall, this study establishes SLC38A5 as a metabolic immune regulator in glioblastoma and presents a promising Nb-based strategy for overcoming αPD-1 immunotherapy resistance.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"13 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088298","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}
Cancer researchPub Date : 2026-10-05DOI: 10.1158/0008-5472.can-26-0297
Ye Eun Hwang, Eunae You, Jinho Kim, Seula Keum, Jangho Jeong, Seongeun Song, Minwoo Lee, Sunghyun Kim, Chung-Hyun Cho, Mineui Hong, Jin Kyung Rho, Jung-Woong Kim, Sangmyung Rhee
{"title":"Stromal MTHFD2 Links Fibrotic Remodeling to Immune Evasion via Redox-Dependent Inflammatory Signaling in Lung Adenocarcinoma","authors":"Ye Eun Hwang, Eunae You, Jinho Kim, Seula Keum, Jangho Jeong, Seongeun Song, Minwoo Lee, Sunghyun Kim, Chung-Hyun Cho, Mineui Hong, Jin Kyung Rho, Jung-Woong Kim, Sangmyung Rhee","doi":"10.1158/0008-5472.can-26-0297","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0297","url":null,"abstract":"Fibroblast activation and extracellular matrix stiffening are hallmarks of the fibrotic tumor microenvironment. Fibrotic microenvironmental remodeling is also linked to immune exclusion and evasion, suggesting that common microenvironmental signals might coordinate both fibrotic and inflammatory outputs. Here, we identified methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) as a redox-sensitive metabolic regulator linking TGF-β-driven fibroblast activation to inflammatory signaling in lung adenocarcinoma (LUAD). MTHFD2 was elevated in cancer-associated fibroblasts across multiple scRNA-seq datasets, and TGF-β induced MTHFD2 even under compliant matrix conditions, with matrix stiffening further enhancing its expression. Notably, while MTHFD2 knockdown suppressed both myofibroblastic and inflammatory programs, enforced expression was sufficient to drive inflammatory cytokine production even in the absence of TGF-β, and this response was further amplified by concomitant TGF-β signaling. These MTHFD2-mediated responses depended on redox perturbation rather than biosynthetic one-carbon metabolism, as they resisted formate supplementation but responded to pro-oxidants. Mechanistically, MTHFD2-driven redox imbalance promoted mitochondrial stress, cytosolic mitochondrial DNA accumulation, and activation of the cGAS–STING–NF-κB pathway, resulting in IL-6 and IL-8 production. Fibroblast-specific MTHFD2 knockdown suppressed paracrine PD-L1 induction in tumor cells and inhibited tumor growth in vivo in an immune-dependent manner. Clinically, high stromal MTHFD2 correlated with epithelial PD-L1 expression and poor LUAD prognosis. Together, these findings identify stromal MTHFD2 as a redox-sensitive metabolic checkpoint linking fibrotic remodeling to immune evasion.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"12 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086753","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":"PLA1A Inhibition Enhances Chemoimmunotherapy Efficacy by Blocking Immunosuppressive Macrophage Polarization in Colorectal Cancer","authors":"Ting-Ting Wang,Wei-Shuai Kong,Jia-Jun Li,Ying-Yu Qiu,Ren-Ze Huang,Hao-Jie Chen,Xiao-Tong Duan,Ping Chen,Yi-Chen Xie,Hai-Yu Mo,Yang Xuan,Yi Han,Kun Liao,Zhao-Lei Zeng,Feng-Hua Wang,Yu-Hong Li,Qiang Gao,Huai-Qiang Ju","doi":"10.1158/0008-5472.can-26-0955","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0955","url":null,"abstract":"Abstract Clinical outcomes are often suboptimal in colorectal cancer (CRC) patients treated with neoadjuvant chemotherapy (NAC). A key determinant of the response to NAC is the functional state of tumor-infiltrating immune cells. Understanding how NAC reshapes the immunological landscape will be essential for refining patient stratification and identifying effective combination treatment strategies. Here, we analyzed paired samples before and after NAC treatment by single-cell RNA sequencing, revealing that NAC treatment significantly reshaped the immune microenvironment. Tumors from NAC non-responders featured increased immunosuppressive M2-like macrophage infiltration, which correlated with elevated phosphatidylserine-specific phospholipase A1 (PLA1A). Mechanistically, PLA1A hydrolyzed phosphatidylserine (PS) exposed by chemotherapy to elevate lysophosphatidylserine (LysoPS), which activated the P2ry10 receptor and downstream signaling to promote M2-like macrophage polarization. Importantly, pharmacological inhibition of PLA1A by cilengitide synergized with chemoimmunotherapy to suppress tumor progression in murine models. Clinically, high plasma PLA1A levels negatively correlated with responses to chemoimmunotherapy. Collectively, these findings reveal a chemotherapy-driven metabolic axis that induces an immunosuppressive milieu by increasing lysoPS release. This axis highlights PLA1A as a therapeutic target to mitigate immunosuppression and improve chemoimmunotherapy efficacy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"58 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088297","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":"Getting comfortable: clonal haematopoiesis creates a senescent niche for expansion","authors":"Nieves Garcia-Gisbert, Giovanna Mantica, Elisa Laurenti","doi":"10.1158/0008-5472.can-26-4171","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-4171","url":null,"abstract":"Clonal haematopoiesis (CH) is characterized by the age-associated expansion of mutant haematopoietic clones. How these clones expand, interact with the niche, and maintain a competitive advantage remains poorly understood. In a recent study published in Nature Cell Biology, Mistry and colleagues uncover that senescence in the bone marrow stromal microenvironment is a key contributor to the clonal growth of haematopoietic stem and progenitor cells (HSPCs) carrying CH mutations. Using mouse models and primary human samples, they show that mutant haematopoietic cells induce MSC senescence through contact-independent, cytokine-mediated signalling involving TNF-α, IL-6 and STAT3. Senescent MSCs preferentially support mutant haematopoietic stem and progenitor cells (HSPCs) over wild-type cells. Moreover, genetic or pharmacological depletion of senescent non-haematopoietic cells reduces CH burden and delays progression towards myeloid neoplasia in mice. By demonstrating that the premalignant niche is actively remodelled to favor mutant haematopoiesis, this study identifies MSC senescence as a relevant mechanism regulating CH evolution and a potential target for early disease intervention.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"32 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086751","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}
Cancer researchPub Date : 2026-10-05DOI: 10.1158/0008-5472.can-26-0389
Shuyuan Zhang, Polly J. Phillips-Mason, Bartosz Mucha, Marganit Farago, Guofang Zhang, Cecilia Martin, Andres J. Klein-Szanto, Hiroshi Nakagawa, Anil K. Rustgi, Kwok-Kin Wong, Brian S. Henick, J. Alan. Diehl
{"title":"Aberrant Accumulation of Cyclin D1 Rewires Glutamine Metabolism and Generates a Metabolic Vulnerability in Squamous Cell Carcinoma","authors":"Shuyuan Zhang, Polly J. Phillips-Mason, Bartosz Mucha, Marganit Farago, Guofang Zhang, Cecilia Martin, Andres J. Klein-Szanto, Hiroshi Nakagawa, Anil K. Rustgi, Kwok-Kin Wong, Brian S. Henick, J. Alan. Diehl","doi":"10.1158/0008-5472.can-26-0389","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0389","url":null,"abstract":"Excessive cyclin D1 accumulation is a frequent oncogenic event in head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). Although classically associated with enhanced proliferation and genomic instability, we revealed that cyclin D1 dysregulation induces metabolic rewiring that leads to unexpected metabolic dependencies. Sustained nuclear retention of cyclin D1 drove metabolic reprogramming through activation of CDK4/6 and downregulation of mitochondrial isocitrate dehydrogenase 3 (IDH3), reducing α-ketoglutarate and NADH production. This metabolic alteration increased glutamine dependence and elevated autophagic flux, and co-targeting autophagy and glutamine metabolism suppressed the growth of squamous cell carcinoma models in vitro and in vivo. Together, these findings highlight a therapeutic strategy for HNSCC and ESCC that leverages metabolic reprogramming induced by dysregulated cyclin D1/CDK4 activity, with potential applicability to patients with tumors refractory to conventional therapies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"11 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086735","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}
Cancer researchPub Date : 2026-10-02DOI: 10.1158/0008-5472.can-26-0801
Lucas Porras, Marina Carrière, Ann-Sophie Gironne, Hugo Philippeau, Gabriel Alzial, Elise Quadri, Jeanne Cormery, Yousef Alaessa, Anie Monast, Faustine Gorse, Myriame St-Arnaud, Mariana De Sa Tavares Russo, Sylvie Nathalie Christine. Mader, Daina Z. Avizonis, Sébastien Lemieux, Morag Park, Geneviève Deblois
{"title":"EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing Triple-Negative Breast Cancer to Glutaminase Targeting","authors":"Lucas Porras, Marina Carrière, Ann-Sophie Gironne, Hugo Philippeau, Gabriel Alzial, Elise Quadri, Jeanne Cormery, Yousef Alaessa, Anie Monast, Faustine Gorse, Myriame St-Arnaud, Mariana De Sa Tavares Russo, Sylvie Nathalie Christine. Mader, Daina Z. Avizonis, Sébastien Lemieux, Morag Park, Geneviève Deblois","doi":"10.1158/0008-5472.can-26-0801","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0801","url":null,"abstract":"EZH2, the catalytic subunit of the histone methyltransferase complex PRC2, is overexpressed and associated with poor prognosis in triple-negative breast cancer (TNBC). Although EZH2 inhibition significantly alters chromatin landscapes and gene expression, it has limited impact on the growth of TNBC models, suggesting adaptive compensatory mechanisms. Here, we demonstrated that EZH2 inhibition causes the accumulation of misfolded proteins and double-stranded RNA (dsRNA), triggering an essential integrated stress response (ISR) through PKR and PERK activation. By inducing ISR-mediated ATF4, EZH2 inhibition enhanced amino acid flux and promoted glutaminolysis to support TNBC cell survival. Pharmacological targeting of this metabolic axis with a glutaminase inhibitor in combination with EZH2 inhibition significantly impaired TNBC cell proliferation and tumor growth. These findings reveal a stress-driven metabolic adaptation that sustains TNBC survival upon EZH2 blockade and highlight inhibition of this pathway as a strategy to enhance the efficacy of EZH2 inhibitors in TNBC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"11 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086345","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}
Cancer researchPub Date : 2026-10-02DOI: 10.1158/0008-5472.can-26-1315
Vishnu Kumarasamy, Jianxin Wang, Edwin H. Yau, Ethan V. Abel, Agnieszka K. Witkiewicz, Erik S. Knudsen
{"title":"Targeting Distinct Cell Cycle Nodes Overcomes RAS Inhibitor Resistance","authors":"Vishnu Kumarasamy, Jianxin Wang, Edwin H. Yau, Ethan V. Abel, Agnieszka K. Witkiewicz, Erik S. Knudsen","doi":"10.1158/0008-5472.can-26-1315","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-1315","url":null,"abstract":"Activating mutations in KRAS drive pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Although mutant-selective KRAS inhibitors and pan-RAS inhibitors provide clinical benefits, the development of resistance limits durable responses. Here, transcriptomic and proteomic analyses revealed that, despite effective suppression of mutant KRAS signaling, resistant cells sustain cell cycle progression. Distinct orthogonal mitogenic pathways were engaged in a context-dependent manner to bypass KRAS inhibition. While these pathways could be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation was uncoupled from RAS signaling. Combinatorial drug screens and genome-wide CRISPR-Cas9 screens showed that perturbing cell cycle nodes via targeting cyclin dependent kinases CDK4/6 and CDK2 restored sensitivity to KRAS/RAS inhibitors. Co-targeting CDK4/6 induced G1 arrest and suppressed E2F-regulated proteins across all resistant models. In contrast, co-targeting CDK2 exerted a broader effect by impairing DNA replication, inducing G2 arrest, preventing mitotic entry, and yielding a more durable cytostatic response that delayed cellular outgrowth after drug withdrawal. Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yielded durable tumor control in vivo in xenografts derived from models with acquired resistance. In conclusion, these findings identify sustained cell cycle activity as a defining feature of resistance to KRAS-directed therapies and establish cell cycle co-targeting as an effective strategy to overcome KRAS/RAS inhibitor resistance.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"93 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086342","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":"Placenta-Related PEG10 Inhibits mRNA Decay to Promote Glucose Metabolism and Tumor Progression in Hepatocellular Carcinoma","authors":"Xinyi Yao, Bi Wu, Caini Yang, Zhaoyu Lin, Mengting Zhang, Shuang Tao, Jie Chen, Yongxin Huang, Xuyao Chen, Yun Li, Yuntan Qiu, Duanqing Tian, Chengyu Jia, Jingyuan Zhang, Daning Lu, Rui Zhang, Yin Zhang, Dong Yin","doi":"10.1158/0008-5472.can-26-0490","DOIUrl":"https://doi.org/10.1158/0008-5472.can-26-0490","url":null,"abstract":"Tumors display marked similarities with embryos, exploiting embryonic developmental programs. Beyond the embryo, the placenta also shares features with malignant tumors, such as invasion, immune evasion, and rapid nutrient exchange, highlighting the need for mechanistic investigations of tumor development through the lens of placental biology. In this study, by screening placental-specific genes with aberrant expression in hepatocellular carcinoma (HCC), we found that the paternally expressed gene 10 (PEG10, a retrovirus-like gene) was overexpressed in HCC and associated with poor patient prognosis. Liver-specific deletion of Peg10 significantly impeded hepatocarcinogenesis and tumor progression in a hydrodynamic tail vein injection-induced HCC mouse model. PEG10 drove tumor cells to co-opt the metabolic phenotype of trophoblast cells by upregulating key glucose metabolic regulators glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Mechanistically, as an RNA-binding protein (RBP), PEG10 inhibited the Staufen1-mediated mRNA decay (SMD) pathway, stabilizing GLUT1 and HK2 mRNA to enhance glucose uptake and aerobic glycolysis. Furthermore, retinoic acid pharmacologically suppressed PEG10 expression, effectively abrogating the adaptive metabolic advantage and acting synergistically with sorafenib to restrict tumor growth. Collectively, this study reveals how HCC aberrantly reactivates the placental gene PEG10 to orchestrate oncogenic glucose uptake and metabolism, identifying it as a compelling therapeutic target for metabolic intervention in cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"60 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149086340","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}
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