Discover. Oncology最新文献

{"title":"Epitranscriptomic regulation of mRNAs and noncoding RNAs by m6A in hepatocellular carcinoma.","authors":"Xinning Luo, Cuiying Qin, Yi Feng, Ganlu Deng","doi":"10.1007/s12672-026-05612-x","DOIUrl":"https://doi.org/10.1007/s12672-026-05612-x","url":null,"abstract":"<p><p>N6-methyladenosine (m6A) is a major epitranscriptomic modification of RNA that plays a crucial role in regulating RNA metabolism and function, thereby participating in diverse biological processes such as cellular homeostasis and stress responses. The dynamic regulation of m6A is orchestrated by three classes of proteins: methyltransferases that install the modification, demethylases that remove it, and m6A-binding proteins that recognize modified transcripts and mediate downstream effects. Accumulating evidence has shown that dysregulation of m6A is critically involved in the initiation and progression of various malignancies. Hepatocellular carcinoma (HCC), a primary liver malignancy with high mortality and poor prognosis, has also been closely linked to m6A-mediated RNA regulation. In this review, we summarize the molecular mechanisms by which m6A regulates both coding and noncoding RNAs in HCC, highlight the functional roles of key m6A regulators in hepatocarcinogenesis, and discuss the therapeutic potential of targeting the m6A machinery in HCC.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An immunogenic cell death-based signature predicts prognosis and immune landscape in triple-negative breast cancer.","authors":"Xiyao Zhang, Miao Cao, Lulu Wu, Yang Zhao","doi":"10.1007/s12672-026-05613-w","DOIUrl":"https://doi.org/10.1007/s12672-026-05613-w","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Triple-negative breast cancer (TNBC) represents a breast cancer subtype lacking three essential biomarkers: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This biological signature differentiates TNBC from other breast cancer subtypes and acts as an essential diagnostic criterion for clinical identification and constitutes essential diagnostic criteria for clinical identification. Among all subtypes of breast cancer, TNBC exhibits an exceptionally high level of aggressiveness. Its aggressive behavior and paucity of effective treatment options contribute to its notoriously poor prognosis. The immunogenic cell death (ICD) emergence has raised hopes to create fresh treatment approaches to strengthen TNBC patients' immune responses against tumors. However, the correlation between ICD and TNBC prognosis is still unclear.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;By analyzing transcriptomic data through the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), we discovered the differentially expressed genes (DEGs) and linked to ICD in TNBC. A prognostic model utilizing ICD was developed through LASSO regression. Then, we conducted multivariate Cox proportional hazards analysis on the identified DEGs. We used receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analysis to evaluate the model's predictive accuracy. To comprehensively evaluate the clinical relevance of the ICD signature, we investigated its associations with genomic alterations, tumor microenvironment (TME) characteristics, and therapeutic responses to both chemotherapy and immunotherapy. Furthermore, functional validation was performed using MDA-MB-231 and BT-549 through various in vitro assays, including CCK-8 proliferation tests, colony formation assays, and Transwell migration experiments to assess HEYL's biological role.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;A 4-gene ICD signature (HEYL, CXCL13, GBP2, and IL22RA2) was developed and stratified TNBC patients into two categories, showing major distinctions in overall survival (OS). We found that higher-risk patients had less favorable results. Meanwhile, they usually had different TMEs with less immune cell infiltration. By contrast, the low-risk group appeared to react better to immunotherapy, as evidenced by their increased immune cell infiltration level and more favorable outcomes. Analysis via the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) uncovered that DEGs were predominantly involved in immune-related pathways, for example, the receptors on the plasma membrane. Additionally, a lower immunological phenotype score (IPS) and increased susceptibility to various chemotherapeutic medicines, including A-443,654, BAY 61-3606, and CP466722, were detected in the low-risk category. Additionally, HEYL knockdown markedly suppressed TNBC cell growth and metastatic capability, whereas its overexpression produced the ","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting liver cancer stem cell heterogeneity via single-cell RNA sequencing and developing a stemness-based prognostic model.","authors":"Jinhan Zhao, Jiaqi Feng, Pengpeng Zhang, Xinyi Wu, Bin Zhang, Lichao Sun","doi":"10.1007/s12672-026-05589-7","DOIUrl":"https://doi.org/10.1007/s12672-026-05589-7","url":null,"abstract":"<p><strong>Background: </strong>Liver cancer stem cells (CSCs) play a pivotal role in the initiation, progression, and recurrence of hepatocellular carcinoma (HCC), but their molecular and metabolic heterogeneity remains largely undefined. Characterizing subpopulations with enriched stemness features is crucial for understanding liver cancer biology and developing targeted therapies.</p><p><strong>Methods: </strong>We integrated two single-cell RNA sequencing datasets (GSE149614 and GSE156625) of HCC to identify malignant cell subpopulations through clustering and annotation. Mitochondrial scoring, CytoTRACE, pseudotime, and pathway enrichment analyses were employed to systematically assess stemness-related features and metabolic features of each cluster. Survival analysis and prognostic modeling based on key cluster signature genes led to the development and validation of the Cluster 3 and Cluster 4 Stemness-based Prognostic Signature (C3C4-SPS).</p><p><strong>Results: </strong>A total of 4,155 malignant cells were re-clustered into eight subpopulations, as revealed by tSNE visualization, highlighting pronounced intratumoral heterogeneity. Mitochondrial scoring demonstrated that Cluster 3 and Cluster 4 had significantly higher metabolic activity than other clusters. CytoTRACE analysis identified higher enrichment of stemness-associated features in these two clusters, and pseudotime trajectory analysis located them at the origins of distinct differentiation pathways, suggesting that they may represent stemness-enriched subpopulations, though this interpretation requires experimental confirmation. Functional enrichment revealed that Cluster 3 was predominantly involved in oxidative phosphorylation (respiratory electron transport chain and ATP synthesis), whereas Cluster 4 was more active in mitochondrial fatty acid β-oxidation and tRNA aminoacylation pathways. Both clusters showed high expression of core stem cell markers (POU5F1, SOX2, MYC, CD44). Multi-cohort survival analyses demonstrated that high expression of signature gene sets from Cluster 3 and Cluster 4 was closely associated with unfavorable prognosis in HCC patients. The C3C4-SPS model effectively stratified patients by risk, with high-risk groups exhibiting significantly worse outcomes, and performed robustly in ROC and PCA validation.</p><p><strong>Conclusion: </strong>This study systematically characterized the molecular and metabolic heterogeneity of liver cancer stem cell subpopulations and elucidated their decisive roles in tumor progression and patient prognosis. These findings are primarily based on computational analyses and warrant further experimental validation. The C3C4-SPS model provides a novel tool for prognostic assessment and potentially individualized therapy targeting stemness-associated features in hepatocellular carcinoma.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZFP36 suppresses lung adenocarcinoma progression by mediating ROS-induced autophagy and ferroptosis.","authors":"Li Li, Yiru Yin, Zixuan Zhang, Xiaoyu He","doi":"10.1007/s12672-026-05597-7","DOIUrl":"https://doi.org/10.1007/s12672-026-05597-7","url":null,"abstract":"<p><strong>Background and objective: </strong>As a tumor suppressor in lung adenocarcinoma (LUAD), ZFP36 is an RNA-binding protein that destabilizes oncogenic mRNAs. However, the precise mechanisms underlying its tumor-suppressive function remain mostly unexplored. The study aims to explore the molecular mechanisms by which ZFP36 suppresses LUAD progression through regulating reactive oxygen species (ROS)-mediated ferroptosis and autophagy.</p><p><strong>Methods: </strong>Real-time quantitative PCR and Western blotting were utilized to investigate ZFP36 expression in cell lines, adjacent normal tissues, and LUAD tissues. Using MTT, colony formation, and apoptosis assays, the impact of ZFP36 overexpression or knockdown on cell proliferation and apoptosis was evaluated. ROS levels and ferroptosis-related markers (MDA, 4-HNE, total iron, and Fe²⁺) were measured in A549 cells. Proteins associated with ferroptosis and autophagy were evaluated for expression using Western blotting.</p><p><strong>Results: </strong>ZFP36 expression was markedly reduced in LUAD cell lines and tissues (P < 0.05). ZFP36 overexpression triggered autophagy and ferroptosis, apoptosis, and inhibited cell proliferation in A549 cells (P < 0.05). Mechanistically, ZFP36 upregulated ROS levels, which in turn induced autophagy and ferroptosis-associated changes, as indicated by increased Beclin-1, ATG5, and the LC3B-II/LC3B-I ratio, ACSL4, and lipid peroxidation markers, along with decreased GPX4 and SLC7A11 expression (P < 0.05).</p><p><strong>Conclusion: </strong>ZFP36 suppresses LUAD progression by promoting ROS-mediated autophagy and ferroptosis-associated changes. As per the results, ZFP36 may be a useful biomarker and treatment target for the treatment of LUAD.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-proliferation effects of oxaliplatin in combination with the probiotic Lactobacillus acidophilus in colorectal cancer cells.","authors":"Saba Hajazimian, Alireza Isazadeh, Farshid Oruji, Shima Shabani","doi":"10.1007/s12672-026-04757-z","DOIUrl":"https://doi.org/10.1007/s12672-026-04757-z","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy is prevalent as a key therapeutic method in the field of cancer treatment. However, the efficacy of colorectal cancer therapy is diminished because of the emergence of drug resistance. Combination therapies that have synergistic advantages present a more promising outlook. This study aimed to evaluate a new strategy for enhancing the anticancer effectiveness of oxaliplatin (OXA) against colorectal cancer cells by concurrently administering probiotic Lactobacillus acidophilus (LA) extraction.</p><p><strong>Methods: </strong>We investigated the effects of OXA, LA extraction, and their combined treatment (OXA-LA) on the viability of the Caco-2 colorectal cancer cell line. The assessment of the metastatic potential of cancer cells involved the application of wound healing assays and transwell migration experiments. Flow cytometry was employed to compare the apoptotic state of cells in the research group. In addition, metastatic and apoptotic gene expression were evaluated using real-time PCR.</p><p><strong>Results: </strong>The viability of colorectal cancer cells was significantly diminished by administration of OXA, LA, and the OXA-LA combination. There was a significant increase in apoptosis observed throughout treatment groups. The co-administration of OXA and LA exhibited enhanced apoptotic and anticancer potency compared to the separate administration of each compound alone. Following the therapy administration, a discernible modification in the expression of genes linked to apoptosis and metastasis was observed.</p><p><strong>Conclusions: </strong>Our study indicated that simultaneous administration of the OXA-LA combination can enhance therapeutic efficacy while concurrently reducing adverse side effects by decreasing the dosage of OXA.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated scissor and CIBERSORTx analyses reveals fibroblast subpopulations and biomarkers in stomach adenocarcinoma.","authors":"Siyi Wu, Manzhong Cai, Jiajia Cai, Yong'an Chen","doi":"10.1007/s12672-026-05584-y","DOIUrl":"https://doi.org/10.1007/s12672-026-05584-y","url":null,"abstract":"<p><strong>Background: </strong>Stomach adenocarcinoma (STAD) represents a significant global health challenge, characterized by high heterogeneity in its tumor microenvironment. This study aimed to create a cell composition assessment tool and identify STAD-associated biomarkers by combined analysis of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data.</p><p><strong>Methods: </strong>A new signature matrix was constructed using CIBERSORTx for deconvolution analysis to gauge cell subpopulation proportions in bulk RNA-seq cohorts, followed by survival analysis to identify key cells. Weighted gene co-expression network analysis (WGCNA) was implemented to recognize key cell-related genes, which were further combined with differential expression analysis and survival analysis to determine biomarkers. Functional characterization was explored through enrichment analysis. The expression differences of biomarkers between STAD and normal groups were detected by quantitative real time polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC).</p><p><strong>Results: </strong>Fibroblasts were identified as the cell type most associated with STAD survival, among which cell-substrate junction fibroblasts (SJFs) were identified as the key subpopulation using our custom CIBERSORTx signature matrix. In patients with STAD, low expression levels of cysteine and glycine-rich protein 1 (CSRP1), lipoma-preferred partner (LPP), Nexilin (NEXN), palladin cytoskeletal associated protein (PALLD), and transforming growth factor beta 1-induced transcript 1 (TGFB1I1) were significantly associated with higher survival rates, indicating that low expression of these biomarkers predicted favorable prognosis. Functional analysis revealed that these biomarkers were involved in oxidative phosphorylation and Wnt signaling pathways. Moreover, CSRP1, LPP, NEXN, PALLD and TGFB1I1 were significantly upregulated in STAD samples at both mRNA and protein levels.</p><p><strong>Conclusion: </strong>Characterization of cellular composition via a custom signature matrix identified SJFs as a key subpopulation in the STAD tumor microenvironment. The identified biomarkers (CSRP1, LPP, NEXN, PALLD, and TGFB1I1) offered valuable insights into STAD microenvironment regulation. Trial registration Not applicable.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early kinetics of CA19-9 and CEA after 5-FU-based chemotherapy for gastrointestinal cancers.","authors":"Sebastian Lange, Patrick Wenzel, Christof Winter, Jürgen Ruland, Roland M Schmid, Hana Algül, Michael Quante, Mathias Friedrich","doi":"10.1007/s12672-026-05570-4","DOIUrl":"10.1007/s12672-026-05570-4","url":null,"abstract":"<p><strong>Introduction: </strong>In gastrointestinal oncology, serum tumor markers such as CEA and CA19-9 are typically monitored over several weeks to assess therapeutic efficacy. The immediate impact of cytotoxic therapy on these serum tumor markers, however, remains poorly characterized.</p><p><strong>Methods: </strong>We analyzed a single-center cohort of patients with advanced gastrointestinal cancers (pancreatic, biliary, colorectal, and esophageal) treated with 5-fluorouracil-based regimens. Paired serum samples were collected immediately before the start of chemotherapy (0 h) and at the removal of the 48-h 5-FU continuous pump (48 h). The primary endpoint was the percentage change of tumor markers during this time window (∆CEA and ∆CA19-9). Secondary endpoints included the association of these acute kinetics with subsequent radiographic response.</p><p><strong>Results: </strong>78 cycles of 5-FU-based chemotherapy were included (33 patients, median cycles per patient: 2). CA19-9 increased significantly after chemotherapy (median ∆CA19-9 + 4.8% per patient, Wilcoxon p = 0.015; mixed model p = 0.062; cycle-level range - 11% to + 92%), as did LDH (median ∆LDH + 12.8% per patient, both Wilcoxon and mixed model p < 0.001; cycle-level range - 39% to + 72%). CEA levels remained stable (median ∆CEA - 3.6% per patient, Wilcoxon p = 0.09; mixed model p = 0.05; cycle-level range - 20% to + 22%). There was no statistically significant association between early changes in serum tumor markers and radiographic outcome.</p><p><strong>Discussion: </strong>In this hypothesis-generating study, 5-FU-based therapy leads to a statistically significant increase in CA19-9 and LDH levels, but not in CEA, after 48 h. The magnitude of the increase did not predict radiographic response.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":"17 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13373114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiome and peptide alterations in children with acute lymphoblastic leukemia: current insights and future directions.","authors":"Zuzanna Zakrzewska, Oliwia Boruta, Dominika Skupień, Szymon Skoczeń","doi":"10.1007/s12672-026-05551-7","DOIUrl":"https://doi.org/10.1007/s12672-026-05551-7","url":null,"abstract":"<p><p>Acute lymphoblastic leukemia (ALL) is the most common type of pediatric leukemia, yet the mechanisms of leukemogenesis remain incompletely comprehended. Since the concept of brain-gut-microbiome has been established, microbiota dysbiosis has been considered to potentially impact on development of this cancer. This review focuses on microbiome and peptide alterations. In ALL pediatric patients during the time of diagnosis significant differences in comparison to healthy children were noted. While treatment and prophylaxis used in this group of patients is known to have an impact on gut microbiome, some changes in bacteria abundances could serve as predictors for infectious complications (e.g. Bifidobacterium longum), however it is not a standard practice. Probiotic supplementation with Bifidobacterium breve or Lactobacillus rhamnosus could reduce adverse symptoms of chemotherapy, but the legitimacy of their use in immunocompromised patients is controversial. Introducing new strategies, such as fecal microbiota transplantation (FMT) could lead to improvement in patients' outcomes in ALL treatment. The interaction between metabolic hormones, peptides and interleukins seems to be crucial for cancer cell metabolism and proliferation as well as immune regulation, inflammation and treatment response. Moreover, gut microbiota does not fully recover in the first year after treatment and even asymptomatic adult survivors of childhood ALL were found to have significantly altered abundances of bacteria species.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A bibliometric analysis of exosome research in colorectal cancer from 2010 to 2024.","authors":"Zimeng Chen, Xuan Xu, Lin Ye","doi":"10.1007/s12672-026-05582-0","DOIUrl":"https://doi.org/10.1007/s12672-026-05582-0","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Exosomes have emerged as key mediators in CRC pathogenesis and progression. However, a systematic overview of the research landscape is lacking. This study aimed to conduct a comprehensive bibliometric analysis to investigate global publication trends and research hotspots in exosome-based CRC research from 2010 to 2024.</p><p><strong>Methods: </strong>Publications were retrieved from the Web of Science Core Collection (WoSCC) and Scopus databases. After screening, deduplication, and merging, eligible studies (English-language articles and reviews published between 2010 and 2024) were included. Bibliometric analyses were performed using VOSviewer and CiteSpace. Clinical trials were additionally retrieved from PubMed to assess translational progress.</p><p><strong>Results: </strong>A total of 3,018 publications were included. Annual publication output showed a steady increase, with a marked acceleration after 2016 (linear trend R² = 0.8607). Research originated from 100 countries. China contributed the most publications (933, 49.5%), while the United States ranks among the top in average citations per article (79.8). The most prolific authors published at least 13 articles. High-frequency keywords included \"exosome miRNA\", \"liquid biopsy\", and \"Fusobacterium nucleatum\". Citation burst analysis identified \"drug delivery\" and \"immunotherapy\" as emerging frontiers. Only six clinical studies were identified, all at early phases, with no exosome-based therapeutic having entered late-phase development.</p><p><strong>Conclusion: </strong>Exosome research in CRC has evolved steadily over the past 15 years, shifting from basic biology toward translational applications. Exosomes show promise as diagnostic/prognostic biomarkers, therapeutic targets, and drug delivery vehicles, but clinical translation remains at an early stage.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chk1 inhibition emerges as the most effective partner for PARP inhibition in BRCA-proficient pancreatic cancer.","authors":"Yoshihito Morimoto, Yohei Musha, Osamu Takeuchi, Hiroshi Inano, Kazuhiro Watanabe, Masayoshi Hirohara, Yutaka Masuda","doi":"10.1007/s12672-026-05581-1","DOIUrl":"10.1007/s12672-026-05581-1","url":null,"abstract":"<p><strong>Background: </strong>PARP inhibitors have shown limited efficacy in pancreatic cancer, partly due to the low prevalence of BRCA mutations, which restricts their clinical use. Because DNA damage checkpoint kinases play critical roles in managing replication stress and DNA damage responses, we investigated whether ATR, Chk1, and WEE1 inhibitors enhance the antitumor activity of olaparib in pancreatic cancer cells, including gemcitabine-resistant clones, and compared these effects with standard chemotherapeutic agents.</p><p><strong>Methods: </strong>Cell viability was evaluated in pancreatic cancer cell lines treated with olaparib in combination with various agents using an MTT assay. Apoptosis was assessed by annexin V and propidium iodide double staining followed by flow cytometry. The combinatorial effects were further examined using an in vivo mouse xenograft model. In addition, the effects of combination therapy were evaluated in gemcitabine-resistant cell clones (BxG140 and BxG400) overexpressing ribonucleotide reductase M1 (RRM1).</p><p><strong>Results: </strong>Co-treatment with olaparib and DNA damage checkpoint inhibitors led to a greater reduction in cell viability than combinations with conventional chemotherapeutics. Notably, olaparib combined with the Chk1 inhibitor prexasertib elicited strong synergistic cytotoxicity in BRCA1/2 wild-type MIA PaCa-2 and BxPC-3 cells, whereas the effect was minimal in BRCA2-deficient Capan-1 cells. Compared with monotherapy, combination therapy markedly enhanced apoptosis and suppressed tumor growth in xenograft models. In gemcitabine-resistant clones, olaparib plus prexasertib downregulated RRM1 expression and restored drug sensitivity through enhanced apoptotic cell death.</p><p><strong>Conclusion: </strong>Combined PARP and Chk1 inhibition exerts potent antitumor activity both in vitro and in vivo in pancreatic cancer models, including BRCA-proficient tumors.</p>","PeriodicalId":11148,"journal":{"name":"Discover. Oncology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}