Cancer letters最新文献

{"title":"TP53-agnostic lethality through combined pan-HDAC and CDK inhibition in acute myeloid leukemia","authors":"Aurélien Pottier ,&nbsp;Sujung Park ,&nbsp;Yejin Lee ,&nbsp;Francesca Liccardo ,&nbsp;Haeun Yang ,&nbsp;Jeonghye Park ,&nbsp;Anne Lorant ,&nbsp;Michael Schnekenburger ,&nbsp;Davide Brusa ,&nbsp;Vladimir Li ,&nbsp;Sergio Valente ,&nbsp;Antonello Mai ,&nbsp;Sarah J. Skuli ,&nbsp;Martin Carroll ,&nbsp;Steffen Boettcher ,&nbsp;Jean-Emmanuel Sarry ,&nbsp;Claudia Cerella ,&nbsp;Franck Morceau ,&nbsp;Marc Diederich","doi":"10.1016/j.canlet.2025.218011","DOIUrl":"10.1016/j.canlet.2025.218011","url":null,"abstract":"<div><div>Tumor protein 53 (TP53)-mutated acute myeloid leukemia (AML) is characterized by poor outcomes and the quick development of treatment resistance. Here, we report that simultaneous inhibition of cyclin-dependent kinases (CDKs) and histone deacetylases (HDACs) with dinaciclib and CAY10603, respectively, eliminates the therapeutic response gap between TP53-mutant and TP53 wild-type AML. Biochemical profiling showed that CAY10603 is not only HDAC6-selective but also exhibits pan-HDAC activity similar to suberoylanilide hydroxamic acid, enabling dual targeting of transcriptional and cell cycle pathways. Across parental wild-type lines and isogenic TP53 mutants, the combination consistently suppressed clonogenic growth, induced caspase-dependent apoptosis, and downregulated key regulators such as CDK2, CDK4/6, and their cyclins, while restoring the CDK inhibitor CDKN1A/p21. In an orthotopic NSG mouse model, dinaciclib + CAY10603 significantly reduced leukemia burden and extended survival without adverse toxicity. By “normalizing” TP53-mutant AML to respond like its wild-type counterpart, this pan-HDAC/multi-CDK blockade offers a TP53-agnostic therapeutic option and warrants clinical evaluation as a strategy that remains effective regardless of baseline allelic status.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218011"},"PeriodicalIF":10.1,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991758","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":"UBE2C promotes pancreatic tumorigenesis by KRAS stabilization via APC/CCDH1-mediated WDR76 degradation","authors":"Linchen Wang ,&nbsp;Xiaoyu Chen ,&nbsp;Ruirui Qu ,&nbsp;Shengpeng Shao ,&nbsp;Longyuan Gong ,&nbsp;Tianqi Li ,&nbsp;Shanghong Jiang ,&nbsp;Yu Lu ,&nbsp;Ying Ma ,&nbsp;Yi Sun ,&nbsp;Danrui Cui ,&nbsp;Xiufang Xiong ,&nbsp;Yongchao Zhao","doi":"10.1016/j.canlet.2025.218013","DOIUrl":"10.1016/j.canlet.2025.218013","url":null,"abstract":"<div><div>Bioinformatics-based association study revealed a strong positive correlation between UBE2C, an E2 ubiquitin-conjugating enzyme, and pancreatic cancer and patient survival. However, whether and how UBE2C plays a causal role in pancreatic tumorigenesis remains elusive. Here, we report that UBE2C functions as a promoter in this process. Specifically, both the mRNA and protein levels of UBE2C are upregulated in pancreatic ductal adenocarcinoma (PDAC), and its levels significantly correlate with poor prognosis. In cell culture models, UBE2C knockdown inhibits the proliferation, survival, migration, and invasion of pancreatic cancer cells, while its overexpression promotes these processes. In <em>in vivo</em> mouse models, <em>Ube2c</em> deletion suppresses pancreatic tumorigenesis and metastasis, driven by Kras^G12D and Kras^G12D;p53^−/−, respectively, thereby significantly extending the lifespan of the mice. Mechanistically, WDR76 couples with CUL1 E3 ligase, rather than CUL4, to promote the degradation of both wild-type and mutant KRAS, thus destabilizing KRAS. In contrast, UBE2C cooperates with APC/C^CDH1 E3 ligase to degrade WDR76 in a KEN-box motif-dependent manner, leading to KRAS accumulation and activation of the MAPK signaling pathway, which drives pancreatic tumorigenesis. Notably, WDR76 levels in pancreatic tissues of Kras^G12D-driven mice decrease as PDAC progresses, while the levels of KRAS^G12D and UBE2C increase. Furthermore, simultaneous WDR76 knockdown via adeno-associated virus (AAV) injection into the pancreatic duct fully rescues RAS/ERK inactivation and PDAC suppression caused by <em>Ube2c</em> deletion, demonstrating a causal role of the UBE2C-WDR76 axis. Collectively, these findings suggest that the UBE2C-WDR76 axis may represent a promising therapeutic target for the treatment of KRAS-driven pancreatic cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218013"},"PeriodicalIF":10.1,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944175","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":"Mapping the tumor immune landscape: single-cell RNA sequencing in cancer immunotherapy","authors":"Yingying Huang ,&nbsp;Mao Zhang ,&nbsp;Qiang Gao","doi":"10.1016/j.canlet.2025.218012","DOIUrl":"10.1016/j.canlet.2025.218012","url":null,"abstract":"<div><div>Single-cell RNA sequencing (scRNA-seq) has emerged as a transformative technology for unraveling the cellular complexity and architecture of diseased tissues. By capturing the transcriptomic profiles of individual cells, scRNA-seq reveals intra-tumoral heterogeneity, distinct immune cell states, and dynamic intercellular interactions, making it particularly valuable in the study of the tumor immune microenvironment (TIME). In recent years, scRNA-seq has been widely adopted in both basic cancer research and clinical applications, advancing our understanding of tumor development, immune regulation, and therapy resistance. These advances have also driven the evolution of computational tools and analytical methods needed to interpret complex scRNA-seq datasets to support the development of precision diagnostics. This review systematically summarizes the core analytical workflows for scRNA-seq data, outlines best practices in data processing, and explores the emerging applications and challenges of this technology in TIME research and translational oncology<strong>.</strong></div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218012"},"PeriodicalIF":10.1,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922040","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 MKK3/c-Myc interaction to overcome osimertinib acquired resistance in EGFR mutant lung cancer","authors":"Zhen Chen ,&nbsp;Karin A. Vallega ,&nbsp;Dongsheng Wang ,&nbsp;Elsa Bildtsen ,&nbsp;Haian Fu ,&nbsp;Suresh S. Ramalingam ,&nbsp;Andrey A. Ivanov ,&nbsp;Shi-Yong Sun","doi":"10.1016/j.canlet.2025.218010","DOIUrl":"10.1016/j.canlet.2025.218010","url":null,"abstract":"<div><div>c-Myc inhibition is a critical mechanism in mediating the therapeutic efficacy of osimertinib against EGFR mutant (EGFRm) NSCLCs and accordingly targeting c-Myc is an effective strategy for overcoming osimertinib acquired resistance, a challenging issue in the clinic. However, lack of specific c-Myc inhibitors restricts the application of this strategy. The current study focused on determining the potential application of an alternative c-Myc inhibitory approach to overcome osimertinib acquired resistance via targeting the MKK3/c-Myc interaction that stabilizes c-Myc protein. SGI-1027, as the first disruptor of MKK3/c-Myc interaction, effectively decreased c-Myc levels via disrupting this interaction and promoting c-Myc degradation in different osimertinib-resistant EGFRm NSCLC cell lines that possessed elevated levels of both c-Myc and MKK3 and increased MKK3/c-Myc interaction. The combination of osimertinib with SGI-1027 synergistically decreased the survival of osimertinib-resistant cells and enhanced apoptosis. Consistently, MKK3 knockdown caused c-Myc reduction and sensitized osimertinib-resistant cells to undergo apoptosis upon osimertinib treatment. Moreover, the SGI-1027 and osimertinib combination was significantly more active than either single agent in suppressing the growth of osimertinib-resistant tumors in mice. In sensitive EGFRm NSCLC cell lines, osimertinib inhibited MKK3 and c-Myc interaction with reduction of c-Myc levels, suggesting a critical mechanism by which osimertinib induces c-Myc degradation. Hence, our findings reveal molecular mechanisms accounting for c-Myc reduction by osimertinib in sensitive EGFRm NSCLC cells and c-Myc elevation in EGFRm NSCLC with acquired osimertinib resistance. Our results also suggest a novel strategy to target c-Myc via disrupting the MKK3/c-Myc interaction to overcome osimertinib acquired resistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218010"},"PeriodicalIF":10.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922041","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":"Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.","authors":"Hunter C Herriage, Cameron L Hughes, Sarah K Fahey, Brian R Calvi","doi":"10.1016/j.canlet.2025.218008","DOIUrl":"10.1016/j.canlet.2025.218008","url":null,"abstract":"<p><p>Polyploid Giant Cancer Cells (PGCCs) occur across multiple cancer types and are associated with therapy resistance, genome instability, disease progression, and metastasis. PGCCs can grow through endocycles, a variant cell cycle of alternating Growth (G) and DNA Synthesis (S) phases without cell division. Unlike programmed endocycles that occur during normal tissue development, PGCCs switch from mitotic cycles to unscheduled endocycles in response to stress. PGCCs can subsequently return to error-prone divisions which generate aneuploid daughter cells that contribute to disease progression. However, the regulation of PGCC cell cycles and contributions to cancer are still being defined. Filling this knowledge gap will lead to the development of improved cancer therapies. In this study, we used a molecular-genetic system in the model organism Drosophila melanogaster to examine how oncogenes interact with unscheduled endocycles in vivo. We found that several oncogenes promote bypass of an endocycle arrest, resulting in increased polyploid cell size and DNA content. The extent of this increased growth was dependent on the type of oncogenic mutation. When these polyploid cells returned to division, Ras^G12V promoted continued divisions of polyploid daughter cells with elevated genome instability. Ras^G12V expression during transient endocycles and subsequent divisions also induced expression of a matrix metalloprotease and a Wnt pathway ligand. Importantly, Ras^G12V with transient endocycles enhanced the growth of large, neoplastic tumors. These findings indicate that oncogenic mutations can synergize with transient, unscheduled endocycles to promote tumorigenesis with important broader implications for cancer prognosis and therapies.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218008"},"PeriodicalIF":10.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12510470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944085","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":"The SOX4-Semaphorin3C axis promotes esophageal adenocarcinoma progression","authors":"Tala Fnu ,&nbsp;Peiguo Shi ,&nbsp;Wanwei Zhang ,&nbsp;Yinshan Fang ,&nbsp;Yosuke Mitani ,&nbsp;Yong Zhang ,&nbsp;Joel Gabre ,&nbsp;Wael Ei-Rifai ,&nbsp;Alexandar Zaika ,&nbsp;Qixuan Chen ,&nbsp;Jian Zhu ,&nbsp;Timothy C. Wang ,&nbsp;Ming Jiang ,&nbsp;Jianwen Que","doi":"10.1016/j.canlet.2025.218005","DOIUrl":"10.1016/j.canlet.2025.218005","url":null,"abstract":"<div><div>Esophageal adenocarcinoma (EAC) is an aggressive malignancy with an approximately 700 % increase in incidence in Western countries over the past four decades. However, the molecular mechanism driving cancer progression remains elusive. In this study we have identified that SOX4, a transcription factor, is enriched in EACs. SOX4 knockdown or deletion leads to a significant reduction in tumor growth and metastasis. Through integrating RNA-Seq and ChIP-Seq we identified Semaphorin 3C (SEMA3C) as an important downstream target of SOX4. Consistently, knockdown of SEMA3C reduced the growth of EAC cells <em>in vitro</em> and xenografts, accompanied by attenuated epithelial-mesenchymal transition. Our findings identifiy a molecular mechanism through which SOX4 regulates SEMA3C to promote tumor progression, offering potential translational therapeutic target (s) for EAC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218005"},"PeriodicalIF":10.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922042","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":"Corrigendum to “Identification of LIMK2 as a therapeutic target in castration resistant prostate cancer” [Cancer Lett 448 (2019)182–196]","authors":"Kumar Nikhil ,&nbsp;Lei Chang ,&nbsp;Keith Viccaro ,&nbsp;Max Jacobsen ,&nbsp;Callista McGuire ,&nbsp;Shakti R. Satapathy ,&nbsp;Michael Tandiary ,&nbsp;Meaghan M. Broman ,&nbsp;Gregory Cresswell ,&nbsp;Yizhou J. He ,&nbsp;George E. Sandusky ,&nbsp;Timothy L. Ratliff ,&nbsp;Dipanjan Chowdhury ,&nbsp;Kavita Shah","doi":"10.1016/j.canlet.2025.217999","DOIUrl":"10.1016/j.canlet.2025.217999","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217999"},"PeriodicalIF":10.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944144","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":"Efficacy and safety of SHR-1701 combined with chemoradiotherapy as neoadjuvant treatment for locally advanced rectal cancer.","authors":"Wentao Tang, Yang Lv, Haiting Xie, Ye Wei, Jian Wang, Mengzhu Yu, Yingyi Jiang, Rongfu Mao, Chuanpei Huang, Shengxiang Rao, Kefeng Ding, Wenju Chang, Guodong He, Jianmin Xu","doi":"10.1016/j.canlet.2025.218006","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.218006","url":null,"abstract":"<p><p>Locally advanced rectal cancer (LARC) remains challenging to treat due to high recurrence rates and limited therapeutic options, particularly for patients with high-risk features. This prospective, multicenter, single-arm, open-label phase 2 trial (ClinicalTrials.gov identifier: NCT05300269) evaluated the efficacy and safety of SHR-1701, a novel bifunctional fusion protein targeting both PD-L1 and TGF-β, in combination with neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) for high-risk LARC. Eligible patients had at least one high-risk factor, including cT3c-d or cT4 tumors, positive mesorectal fascia, extramural vascular invasion, or involvement of ≥4 lymph nodes. Patients received concurrent SHR-1701 and CRT, followed by two cycles of SHR-1701 plus XELOX and subsequent TME surgery. Postoperatively, patients underwent six additional cycles of SHR-1701 plus XELOX. The primary endpoints were pathological complete response (pCR) rate and safety. Among the 37 enrolled patients, 36 (97.3 %) completed the planned full-dose radiotherapy (50.4 Gy in 28 fractions) and subsequently underwent surgery. The pCR rate was 36.1% (13/36). The median intervals from neoadjuvant therapy initiation to surgery and from surgery to adjuvant therapy were 112 days (range, 95-139) and 29 days (range, 22-59), respectively. The median follow-up was 9.9 months (range, 2-18) from the first dose of capecitabine. Grade ≥3 treatment-related adverse events during neoadjuvant therapy occurred in 40.5% (15/37) of patients, most commonly lymphopenia (37.8%, 14/37) and anemia (5.4%, 2/37). One patient experienced fatal immune-mediated myocarditis prior to surgery. Overall, the addition of SHR-1701 to CRT demonstrated encouraging efficacy and manageable safety in high-risk LARC, supporting further investigation in larger randomized trials.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"218006"},"PeriodicalIF":10.1,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944169","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":"Shifts in cancer funding: An overview of terminated research grants at the national cancer institute","authors":"Aakash Reddy ,&nbsp;David T. Zhu","doi":"10.1016/j.canlet.2025.218003","DOIUrl":"10.1016/j.canlet.2025.218003","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218003"},"PeriodicalIF":10.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922043","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":"Extrachromosomal DNA (ecDNA) drives hepatocellular carcinoma malignancy through high-copy amplification of chromosome 1q21-derived PIP5K1A oncogene","authors":"Ni Zhang ,&nbsp;Xiangyu Zhang ,&nbsp;Tinghao Yan ,&nbsp;Fen Liu ,&nbsp;Xinchen Tian ,&nbsp;Changlin Ma ,&nbsp;Huapeng Lin ,&nbsp;Yiming Zhang ,&nbsp;Lingli Hao ,&nbsp;Jiaqi Zhang ,&nbsp;Qingxia Xu ,&nbsp;Qingbin Liu ,&nbsp;Shulong Jiang","doi":"10.1016/j.canlet.2025.218004","DOIUrl":"10.1016/j.canlet.2025.218004","url":null,"abstract":"<div><div>Extrachromosomal circular DNA (eccDNA) drives oncogene amplification in multiple malignancies, yet its landscape and clinical relevance in hepatocellular carcinoma (HCC) remain poorly characterized. Here, we performed Circle-seq and RNA-seq on six pairs of HCC tumors and adjacent non-tumor tissues, identifying a 3 Mb extrachromosomal DNA (ecDNA) from chromosome 1q21 in 50 % tumor samples. This ecDNA contained multiple genes, but functional analysis prioritized <em>PIP5K1A</em> due to its central role in <em>PI3K/AKT</em> signaling and association with poor prognosis. The extrachromosomal localization of <em>PIP5K1A</em> was validated through outward PCR, inward PCR, Sanger sequencing, and fluorescence <em>in situ</em> hybridization (FISH) assays. Kaplan-Meier (KM) analysis demonstrated that elevated <em>PIP5K1A</em> expression was associated with an unfavorable prognosis in patients with HCC. <em>In vivo</em> and <em>in vitro</em> assays revealed that ecDNA-driven <em>PIP5K1A</em> amplification enhanced HCC proliferation, migration, and apoptosis resistance. Our study provides a genome-wide eccDNA profiling of HCC, implicating 1q21 ecDNA and <em>PIP5K1A</em> as prognostic markers and therapeutic targets, offering insights into HCC treatment strategies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"633 ","pages":"Article 218004"},"PeriodicalIF":10.1,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906975","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}