Oncogenesis最新文献

{"title":"Multi-omics analysis reveals LARP1 as a key integrator of translation and metabolism in AML.","authors":"Dominik A Nahotko, Brian Lee, Emely Lopez Fajardo, Aneta H Baran, Szymon K Filip, Peter A Faull, Elizabeth T Bartom, Masha Kocherginsky, Peng Gao, Jason Miska, Diana Saleiro, Elspeth M Beauchamp, Leonidas C Platanias","doi":"10.1038/s41389-026-00623-3","DOIUrl":"10.1038/s41389-026-00623-3","url":null,"abstract":"<p><p>La-related protein 1 (LARP1) is an RNA-binding protein and downstream effector of mTOR and CDK9 signaling that regulates translation of mRNAs containing a 5'-terminal oligopyrimidine motif. While elevated LARP1 expression has been linked to poor prognosis in acute myeloid leukemia (AML), its mechanistic role remains unclear. Using CRISPR/Cas9-mediated LARP1 knockout and multi-omics analyses, we investigated LARP1's role in AML. LARP1 loss impaired proliferation, clonogenicity, and tumor growth in xenografts, and enhanced sensitivity of AML cells to 5-azacytidine and cytarabine. Polysome profiling and RNA sequencing revealed that LARP1 modulates a distinct set of transcripts involved in mitochondrial function, amino acid metabolism, and cell cycle regulation, independently of mTOR and CDK9. Proteomics analysis uncovered additional effects of LARP1 loss on immune signaling, lysosomal pathways, and protein stability, including changes not evident at the RNA level. Metabolomic profiling showed reprogramming of arginine/creatine metabolism and depletion of pyrimidine biosynthesis intermediates. Cytidine deaminase, a known resistance factor, was downregulated across omics layers upon LARP1 loss. These findings define LARP1 as a key integrator of translational regulation and metabolic control in AML, supporting leukemic cell survival and promoting drug resistance. Targeting LARP1 may uncover vulnerabilities in leukemia cells, not addressed by current therapies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147960173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic vulnerabilities and therapeutic opportunities in diffuse large B-cell lymphoma.","authors":"Marie Anne-Catherine Neumann, Christian Frezza","doi":"10.1038/s41389-026-00629-x","DOIUrl":"10.1038/s41389-026-00629-x","url":null,"abstract":"<p><p>Diffuse large B cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma (NHL), exhibits considerable biological heterogeneity. While its classification has traditionally relied on genetic and transcriptomic features, emerging evidence points to distinct metabolic subtypes that may represent novel therapeutic vulnerabilities. Intriguingly, current chemoimmunotherapy regimens exert profound but non-specific effects on tumour metabolism, inadvertently exploiting metabolic dependencies yet without precision. Novel inhibitors targeting glucose, amino acid, lipid, and mitochondrial metabolism demonstrate selective cytotoxicity in metabolically defined lymphoma subsets. This review investigates how standard therapies exploit DLBCL metabolism and examines heterogeneity across subtypes, and evaluates targeted metabolic therapies. We discuss emerging combination strategies with current therapeutic regimes and immunotherapy. Particular focus is given to the metabolic interactions between tumour cells and immune effectors, including CAR T cells and bispecific antibodies. We highlight the importance of translational research to validate metabolic subtypes through metabolomic profiling, identify predictive biomarkers, and develop rational combinations. Moving beyond empiric therapy towards strategic metabolic targeting offers an opportunity to enhance outcomes for patients with this aggressive and diverse lymphoma.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"15 1","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13179362/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147948890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SHP1 expression in tumor-associated dendritic cells drives immunoevasion via impairing CD8⁺ memory T cell responses.","authors":"Gao Yu, Yusheng Liang, Weize Yu, Gaojian Zhuang, Bing Li, Jiayi Huang, Jinghao Zheng, Xuanqi Yang, Leyun Wen, Xiaoming Tan, Yuan Zhang","doi":"10.1038/s41389-026-00627-z","DOIUrl":"10.1038/s41389-026-00627-z","url":null,"abstract":"<p><p>Despite the achievements of immunotherapy in the treatment of cancer, overcoming the immune resistance is still an unmet challenge. Dendritic cells (DCs) dysfunction plays a pivotal role in tumor immunoevasion. Previous study uncovered that targeting src homologous region 2 protein tyrosine phosphatase (SHP1) improved anti-PD-1 therapy efficacy in breast cancer by reinvigorating DCs, but the detailed mechanisms remained unclear. Here, we investigated the function of SHP1 in enabling tumor immune escape and suppressing memory T cell formation. Deficiency of SHP1 augmented the activation and antigen-presenting function of dendritic cells, which consequently suppressed the growth of B16-F10 and EMT6 models. We validated this enhanced DC-mediated anti-tumor immunity using conditional knockout mice of SHP1. These results suggested that SHP1 acts as a critical promoter of tumor immune escape. Combining transcriptomic analysis with DC-specific SHP1 deletion, we demonstrated that SHP1 deficiency augments DC immunogenicity via the IFN-γ-JAK1/2-STAT1 pathway. Furthermore, SHP1 blockade promoted the generation of central memory CD8⁺ T cells, through upregulating the expression of TCF-1, a transcription factor essential for memory lineage commitment. In summary, our research identifies SHP1 as a critical intracellular checkpoint that promotes tumor immune evasion by concurrently suppressing DC antigen presentation and the formation of central memory CD8⁺ T cells, nominating it as a promising therapeutic target for immunotherapy-resistant cancers.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13347042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147948973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imbalances of mitochondrial dynamics in solid tumors.","authors":"Carmen Roskam, H Rebecca K Roessler, Jan Paul Medema, Maarten F Bijlsma","doi":"10.1038/s41389-026-00620-6","DOIUrl":"10.1038/s41389-026-00620-6","url":null,"abstract":"<p><strong>Abtract: </strong>In cancer, mitochondrial fission and fusion dynamics are often imbalanced due to altered transcriptional and post-transcriptional control of their key regulators, resulting in either excessive fission or fusion. Despite being opposing processes, these imbalances in mitochondrial dynamics play a critical role in tumorigenic processes. Excessive fission drives metabolic reprogramming by promoting a shift toward aerobic glycolysis and regulating fatty acid metabolism, whereas excessive fusion supports oxidative phosphorylation and glutaminolysis. Both processes, in their own specific way, enable rapid growth and enhance survival in heterogeneous and unfavorable tumor microenvironments. Beyond metabolic regulation, excessive fission plays a key role in invasion and metastasis by promoting cytoskeletal remodeling for single-cell migration and inducing epithelial-to-mesenchymal transition. Moreover, both excessive fission and fusion can inhibit apoptosis and enhance therapy resistance by modulation of the intrinsic apoptosis pathway, upregulation of antioxidant defenses, and/or activation of autophagy. This review examines how both dysregulated fission and fusion contribute to tumorigenic processes in solid tumors and highlights mitochondrial dynamics as a promising therapeutic target.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13333946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147932376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin-specific protease 11 suppresses cuproptosis in colorectal cancer by regulating the ubiquitination and stability of ISCU.","authors":"Hailin Ke, Guowei Zhang, Weili Lin, Yuecui Jiang, Meina Wu, Yueyi Zhang, Weiyang Song, Fuhai Wang, Songling Yan","doi":"10.1038/s41389-026-00621-5","DOIUrl":"10.1038/s41389-026-00621-5","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains one of the most common and deadly malignancies, with limited effective treatment options. Cuproptosis is a novel regulated cell death triggered by mitochondrial copper overload (Cu²⁺) and has been implicated in several cancers. However, the mechanisms governing cuproptosis in CRC are largely unknown. In this study, we investigated the role of ubiquitin-specific proteases (USPs), key regulators of protein stability, in modulating cuproptosis in CRC. Through integrative analysis of publicly available CRC transcriptomic datasets, we identified oncogenic USPs potentially involved in cuproptosis regulation. Among them, USP11 emerged as significantly overexpressed in CRC tissues, and its elevated expression was correlated with poorer patient survival. We next examined the functional role of USP11 in two CRC cell lines and patient-derived CRC organoids. Cells were treated with elesclomol and CuCl₂, a combination known to induce cuproptosis. Functional assays revealed that USP11 promotes cell viability, colony formation, survival, and migration/invasion and suppresses cuproptosis in response to treatment. Mechanistic studies showed that USP11 directly binds to and deubiquitinates ISCU, a scaffold protein essential for iron-sulfur cluster assembly and known to bind Cu²⁺. This deubiquitination stabilizes ISCU, thereby preventing its proteasomal degradation. Rescue experiments further confirmed that ISCU is a key downstream effector mediating USP11's cuproptosis resistance effect. Finally, in patient-derived CRC organoid models, knockdown of USP11 significantly enhanced cuproptosis upon elesclomol/CuCl₂ treatment, validating our in vitro findings. Collectively, our work identifies USP11 as a novel inhibitor of cuproptosis in CRC, acting through the stabilization of ISCU. This newly uncovered USP11-ISCU axis contributes to tumor resistance against cuproptotic stress and highlights a potential therapeutic target for sensitizing CRC to copper-induced cell death.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic modulation of immune cell function: mechanisms and therapeutic implications in cancer immunotherapy.","authors":"Nina Fenouille, Camille Lobry, Lina Benajiba, Alexandre Puissant","doi":"10.1038/s41389-026-00622-4","DOIUrl":"10.1038/s41389-026-00622-4","url":null,"abstract":"<p><p>Immune cell function is remarkably plastic, allowing T cells, NK cells, and macrophages to transition from resting or quiescent states to proliferative, cytotoxic, or inflammatory programs. These functional shifts are tightly coupled to metabolic reprogramming, which not only fuels energy and biosynthesis but also shapes epigenetic and transcriptional landscapes that guide immune responses. In this review, we highlight how intrinsic metabolic pathways which include glycolysis, fatty acid oxidation, amino acid metabolism, and TCA cycle intermediates, regulate T and NK cell proliferation, cytotoxicity, memory formation, and epigenetic programs. We also examine macrophages, whose polarization into pro-inflammatory M1 or tissue-reparative M2 states is orchestrated by distinct metabolic programs such as arginine metabolism, oxidative phosphorylation, and fatty acid oxidation, with consequences for local immune regulation. We then explore how tumors exploit these metabolic dependencies to create hostile microenvironments that restrict nutrients, accumulate immunosuppressive metabolites, and dampen immune cell activity. Finally, we discuss emerging metabolic interventions designed to restore immune fitness, enhance the efficacy of immune checkpoint inhibitors, and improve the persistence and cytotoxicity of adoptive T cell therapies, including CAR-T cells, in nutrient-deprived and hypoxic tumor niches. By linking immune cell plasticity to metabolic control, this review provides a framework for understanding how metabolism shapes immunity and identifies strategies to harness these pathways for next-generation cancer immunotherapies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HPCAL1 promotes colorectal cancer progression via TCF7/p65-mediated Wnt ligand upregulation and Wnt/β-catenin pathway activation.","authors":"Linna Cheng, Huiyang Zhang, Liqun Guo, Qing Zhang, Yuanyuan Zhang, Qi Xie, Shuai Zhou, Dongpeng Wen, Wenchao Chen, Zhikai Wang, Jiancheng Zhang, Rick F Thorne, Zunmin Zhu","doi":"10.1038/s41389-026-00618-0","DOIUrl":"10.1038/s41389-026-00618-0","url":null,"abstract":"<p><p>Abnormal Wnt/β-catenin pathway activation drives colorectal cancer (CRC) tumorigenesis, yet effective targeted therapies remain elusive. Given HPCAL1's established dual tumor-suppressive and oncogenic roles in other cancers, this study investigates its function in CRC to assess the therapeutic potential. Bioinformatic analyses of publicly available CRC datasets supported by in-house cohort studies linked high HPCAL1 expression in primary CRC tissues with clinicopathological factors associated with metastasis and worsened patient outcomes. Knockdown and overexpression studies in cell lines showed that HPCAL1 positively contributes to CRC cell motility and invasion, as well as proliferation in vitro and in vivo in xenografts. RNA sequencing linked HPCAL1 expression with the Wnt/β-catenin pathway, demonstrating positive correlations with Wnt ligands in CRC models and clinical samples. Biochemical approaches showed HPCAL1 augmented the activation and nuclear localization of β-catenin. Moreover, HPCAL1 formed distinct complexes with β-catenin in tandem with the TCF7 or p65 transcription factors, in turn, differentially transactivating Wnt6, Wnt7A, and Wnt11 ligands. Notably, the anticancer activity of desloratadine against CRC cells, a pharmacological inhibitor of HPCAL1, functioned by curtailing Wnt6, Wnt7A, and Wnt11 expression and suppressing Wnt/β-catenin signaling. Collectively, these findings indicate that HPCAL1 is a significant contributor to the clinical aggressiveness of CRC with oncogenic effects intrinsically linked with sustaining canonical Wnt pathway activation. Furthermore, drug targeting experiments provide proof-of-principle evidence for promoting HPCAL1 as a therapeutic target for countering activated Wnt/β-catenin signaling in colorectal cancer.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13316108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 LIMK by Cofilin-1 peptidomimetics enhances actin depolymerization and reduces metastasis of non-small cell lung cancer.","authors":"Min-Ying Lin, Jyh-Der Leu, Chun-Yi Wu, Liang-Cheng Chen, Yi-Jang Lee","doi":"10.1038/s41389-026-00624-2","DOIUrl":"10.1038/s41389-026-00624-2","url":null,"abstract":"<p><p>Metastasis is a major contributor to the mortality and morbidity of human non-small cell lung cancer (NSCLC), driven by actin cytoskeletal rearrangements that enhance cancer cell motility and invasiveness. Cofilin-1 (CFL-1), a key actin-binding protein regulated by LIM kinase (LIMK), controls actin turnover through phosphorylation at serine-3. However, the role of CFL-1 phosphorylation in lung cancer metastasis remains unclear. In this study, in silico analysis revealed that high LIMK/CFL-1 expression correlates with poor prognosis in lung cancer patients. Although total CFL-1 levels were elevated across NSCLC cell lines, its serine-3 phosphorylation showed a stronger association with cellular invasiveness. To therapeutically target this pathway, we developed a cofilin mimetic peptide (CMP) designed to competitively inhibit endogenous CFL-1 phosphorylation. CMP treatment selectively accumulated in LIMK-overexpressing lung cancer cells both in vitro and in vivo, and effectively suppressed actin stress fiber formation by enhancing actin depolymerization. Acting as a competitive decoy of LIMK, CMP reduced cancer cell motility and invasion, and significantly inhibited metastatic progression in orthotopic NSCLC mouse models. Importantly, CMP treatment prolonged survival without inducing systemic toxicity. These findings highlight CFL-1 phosphorylation as a critical driver of lung cancer metastasis and propose peptidomimetic inhibition of the LIMK/CFL-1 pathway as a promising therapeutic strategy for metastatic NSCLC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13284410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming lipid metabolism in pediatric cancers.","authors":"Vinzent L Lindemann, Nazek Noureddine, Raphael J Morscher","doi":"10.1038/s41389-026-00617-1","DOIUrl":"10.1038/s41389-026-00617-1","url":null,"abstract":"<p><p>Metabolic reprogramming is a defining feature of malignant transformation and cancer cell growth. Pediatric cancers arise from genetic disruptions hijacking developmental programs by aberrant transcriptional networks. This coordinated rewiring shapes lipid metabolism through activation of biosynthetic pathways, membrane remodeling, and metabolic flexibility. This review synthesizes recent advances in the understanding of lipid metabolism reprogramming across pediatric cancers, examining four key areas: (1) transcriptional drivers that activate fatty acid and cholesterol synthesis; (2) lipid catabolism sustaining ATP, acetyl-CoA and NADPH pools under metabolic stress; (3) ferroptosis evasion through desaturation pathways and membrane remodeling; and (4) tissue-specific metabolic adaptations enabling metastasis to the bone marrow and cerebrospinal fluid. Despite extensive preclinical evidence identifying targetable vulnerabilities - including dependencies on FASN, SCD, and HMGCR - clinical impact remains to be proven. We discuss challenges of introducing therapies targeting lipid metabolism to the clinic and argue that the future lies in a better understanding of lipid flux and patient-specific dependencies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13276031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147818239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclin E modulates vulnerability to CDC7 kinase inhibition.","authors":"Adam P Dommer, Robert Kyne, Jianxin Wang, Thomas N O'Connor, Amnon Koren, Erik S Knudsen, Agnieszka K Witkiewicz","doi":"10.1038/s41389-026-00613-5","DOIUrl":"10.1038/s41389-026-00613-5","url":null,"abstract":"<p><p>CCNE1 (cyclin E) is frequently amplified or overexpressed in triple-negative breast cancer (TNBC) as compared with luminal subtypes. Cyclin E is associated with chromosomal instability and poor outcome, and overexpression promotes replication stress (fork stalling) in S-phase through impaired MCM chromatin loading and deregulated replication origin firing. Thus, approaches leveraging cyclin E-induced replication stress could lead to the development of promising therapeutic strategies. Here, we studied the effects of cell division cycle 7 (CDC7) kinase inhibition in TNBC cells overexpressing cyclin E. Cyclin E overexpression enhanced sensitivity to CDC7 inhibition, reducing proliferation and colony-forming capacity. This was accompanied by delays in replication timing and cell accumulation with ≥4 N DNA content. Conversely, CCNE1 knockdown rescued proliferation and colony outgrowth in the presence of CDC7 inhibition and reversed accumulation with ≥ 4N DNA content. CRISPR screening revealed cyclin-dependent kinase 8 (CDK8) as conferring resistance to CDC7 inhibition in a CCNE1-amplified cell line. Combined CDC7 and CDK8 inhibition significantly reduced proliferation and colony-forming ability, led to ≥4 N DNA content, and reduced tumor volume and mass in vivo. Together, this work identifies the enhanced vulnerability of cyclin E-overexpressing TNBC cells to CDC7 kinase inhibition and substantial synergy when combined with CDK8 inhibition.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13243581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147777482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}