Cancer Science最新文献

{"title":"Lnc-TPT1-AS1/CBP/ATIC Axis Mediated Purine Metabolism Activation Promotes Breast Cancer Progression","authors":"Yiyun Zhang,&nbsp;Hanyu Zhang,&nbsp;Mingcui Li,&nbsp;Yanling Li,&nbsp;Zhuo-Ran Wang,&nbsp;Weilun Cheng,&nbsp;Yansong Liu,&nbsp;Zhengbo Fang,&nbsp;Ang Zheng,&nbsp;Jingxuan Wang,&nbsp;Fei Ma","doi":"10.1111/cas.70045","DOIUrl":"10.1111/cas.70045","url":null,"abstract":"<p>The purine biosynthetic pathway was recently identified to play a crucial role in breast cancer progression. However, little was known about the regulatory mechanisms of long non-coding RNA in breast cancer purine metabolism. In this study, we discovered that LncRNA TPT1-AS1 (TPT1-AS1) was downregulated in breast cancer tissues. Its introduction in breast cancer cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis suggested that the purine biosynthetic pathway was activated in TPT1-AS1-knockdown MCF-7 cells. Inosine monophosphate (IMP), the product of de novo purine biosynthesis, was significantly upregulated. Mechanistically, we found that TPT1-AS1 could physically interact with CBP (CREB-binding protein), which consequently led to the loss of H3K27Ac in the promoter area of ATIC, the key enzyme of IMP synthesis. This process could block breast cancer purine metabolism and inhibit breast cancer progression. In conclusion, our findings illustrate the role of non-coding RNAs in breast cancer purine metabolism reprogramming and present a potential candidate for breast cancer therapy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1565-1578"},"PeriodicalIF":4.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651500","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":"AmNA-Modified Antisense Oligonucleotide Targeting MCM8 as a Cancer-Specific Chemosensitizer for Platinum Compounds","authors":"Yuki Uchibori,&nbsp;Masaki Suekuni,&nbsp;Yuko Kokaji,&nbsp;Kazumasa Yoshida,&nbsp;Tohru Kiyono,&nbsp;Yuuya Kasahara,&nbsp;Masatoshi Fujita","doi":"10.1111/cas.70024","DOIUrl":"10.1111/cas.70024","url":null,"abstract":"<p>MCM8 and MCM9 participate in homologous recombination with long-tract gene conversion to repair double-strand breaks caused by replication stress, which is generally higher in cancer cells than in normal cells. MCM8 is highly expressed in certain cancer cells, where it is necessary for maintaining cell growth, migration, and invasion, although the molecular mechanisms remain unclear. Knockdown with siRNAs or knockout of MCM8 or MCM9 selectively sensitizes cancer cells to cisplatin. Thus, drugs inhibiting MCM8 or MCM9 could serve as novel anti-neoplastic agents and/or chemosensitizers that selectively sensitize cancer cells to platinum compounds. The present study describes the development of an amido-bridged nucleic acid (AmNA)-modified gapmer antisense oligonucleotide (ASO) targeting <i>MCM8</i>, called ASO 8–3419. In vitro, ASO 8–3419 inhibited MCM8 expression in several human cell lines and selectively sensitized cancer cells to cisplatin. Moreover, ASO 8–3419 modestly suppressed the growth of several cancer cell lines whose proliferation has been reported to depend on MCM8. In vivo, ASO 8–3419 inhibited the expression of MCM8 in xenografted tumors of colon cancer-derived HCT116 cells in nude mice and increased tumor sensitivity to cisplatin with minimal toxicity. These findings suggest that AmNA-modified, MCM8-specific ASOs hold promise as novel anti-cancer agents.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 5","pages":"1405-1416"},"PeriodicalIF":4.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651497","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":"LTF as a Potential Predictive Biomarker for Durable Benefit From First-Line Chemo-Immunotherapy in Small Cell Lung Cancer","authors":"Shimo Shen,&nbsp;Yili Wu,&nbsp;Zhuowei Shao,&nbsp;You Li,&nbsp;Di Peng,&nbsp;Bing Li,&nbsp;Zhou Zhang,&nbsp;Shibo Wu","doi":"10.1111/cas.70049","DOIUrl":"10.1111/cas.70049","url":null,"abstract":"<p>At present, only a limited fraction of patients with extensive-stage small cell lung cancer (ES-SCLC) achieve a sustained response to immune checkpoint blockade (ICB) therapy. The factors that drive therapeutic efficacy remain poorly delineated, and the field is devoid of reliable predictive biomarkers to guide personalized treatment decisions. Therefore, we conducted RNA sequencing of tumor samples from 21 patients prior to treatment to identify expression patterns associated with lasting benefit and used weighted gene co-expression network analysis (WGCNA) to identify key genes associated with favorable outcomes of chemotherapeutic immunotherapy. Multiplex immunofluorescence (mIF) quantification and reanalysis of publicly available datasets were used to validate the hub gene's association with the immune microenvironment and immunotherapy efficacy. The functional significance of the hub gene was further investigated in cellular models. We found that the durable clinical benefit (DCB) group exhibited significantly elevated levels of inflammation and interferon response compared to the no-durable benefit (NDB) group, alongside a notably lower proportion of Tregs and distinct metabolic features. Lactotransferrin (LTF) was identified as a hub gene associated with durable therapeutic benefits in chemo-immunotherapy. By further analysis, we proved that LTF acts as a tumor suppressor in small cell lung cancer, impacting cell proliferation, migration, and invasiveness. It also inhibits lipid metabolism in these cells. Elevated LTF expression is linked to better chemo-immunotherapy outcomes, suggesting its potential as a predictive biomarker for first-line treatment response in ES-SCLC.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1522-1536"},"PeriodicalIF":4.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651502","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":"Claudin-11 Enhances Invasive and Metastatic Abilities of Small-Cell Lung Cancer Through MT1-MMP Activation","authors":"Shuichi Sakamoto,&nbsp;Hiroyuki Inoue,&nbsp;Takahisa Takino,&nbsp;Yasuko Kohda,&nbsp;Junjiro Yoshida,&nbsp;Shunichi Ohba,&nbsp;Ihomi Usami,&nbsp;Takeshi Suzuki,&nbsp;Manabu Kawada,&nbsp;Masanori Hatakeyama","doi":"10.1111/cas.70038","DOIUrl":"10.1111/cas.70038","url":null,"abstract":"<p>Small-cell lung cancer (SCLC) is an aggressive tumor characterized by the frequent development of distant metastases. This study aimed to explore the mechanism of SCLC metastasis using an originally developed orthotopic transplantation model with DMS273 cells. An analysis of G3H cells, a highly metastatic subline of DMS273 cells, revealed that claudin-11 promotes the invasive and metastatic ability of the cells. Further analysis revealed that membrane type 1-matrix metalloproteinase (MT1-MMP), which degrades a wide range of extracellular matrix components, was coprecipitated with claudin-11. Gelatin zymography revealed that claudin-11 enhanced MT1-MMP activity, and <i>MT1-MMP</i> silencing suppressed the invasive and metastatic ability of G3H cells. Moreover, in <i>MT1-MMP</i> silencing DMS273 cells, the enhancement of invasion and metastatic potential induced by <i>CLDN11</i> overexpression was abolished. These results demonstrate that claudin-11 enhances the invasive capacity of the cells by activating MT1-MMP, which promotes metastatic formation in the orthotopic transplantation model. Additionally, claudin-11 expression was detected in SCLC tumor samples, and higher expression of <i>CLDN11</i> correlated with poor prognosis in patients with SCLC. These findings suggest that the claudin-11/MT1-MMP axis plays an important role in SCLC pathogenesis.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1773-1784"},"PeriodicalIF":4.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626374","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":"STAB1 Promotes Acute Myeloid Leukemia Progression by Activating the IKK/NF-κB Pathway and Increasing M2 Macrophage Polarization","authors":"Jiaxiu Yin,&nbsp;Jing Luo,&nbsp;Lan Wang,&nbsp;Lanxiang Liu,&nbsp;Lin Liu","doi":"10.1111/cas.70044","DOIUrl":"10.1111/cas.70044","url":null,"abstract":"<p>As a multifunctional scavenger receptor, stabilin-1 (STAB1) has been identified to induce chronic inflammation and promote cancer progression. Although in silico studies from multiple data sets showed that STAB1 might facilitate the progression of acute myeloid leukemia (AML) and drug resistance, the real impacts of STAB1 expression on AML patients and the detailed mechanisms remain unclear. Herein, we found that a higher expression of STAB1 is associated with a worse prognosis in AML patients. Subsequent in vitro experiments demonstrated that STAB1 knockdown suppressed proliferation and promoted apoptosis through regulating the IKK/NF-κB pathway in human AML cell lines HEL and NB4. In addition, in vivo studies showed that STAB1 silencing prolonged survival, reduced proliferation, and inhibited aggressiveness of AML cells in xenograft mouse models. Moreover, we investigated the impact of STAB1 expression in AML cells on macrophage differentiation and found that co-culture of macrophages with conditioned medium from STAB1-knockdown AML cells reduced M2 polarization of macrophages. Taken together, our study suggests that STAB1 promotes growth and aggressiveness of AML cells through activating the IKK/NF-κB pathway while also regulating M2 macrophage polarization within the chronic inflammatory environment. Therefore, targeting STAB1 could be a potential therapeutic strategy for treating AML.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1508-1521"},"PeriodicalIF":4.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626496","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":"LncRNA-DANCR Promotes ESCC Progression and Function as ceRNA to Regulate DDIT3 Expression by Sponging microRNA-3193","authors":"Heng Xiao,&nbsp;Tong Zhou,&nbsp;Yanfang Yang,&nbsp;Xin Yang,&nbsp;Yanghui Bi,&nbsp;Xiaolong Cheng","doi":"10.1111/cas.70035","DOIUrl":"10.1111/cas.70035","url":null,"abstract":"<p>Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of cancer development and progression. Among them, Differentiation Antagonizing Non-Protein Coding RNA (DANCR) has been implicated in various malignancies, including esophageal squamous cell carcinoma (ESCC). This study explores the clinical characteristics, prognostic implications, functional roles, and molecular mechanisms of DANCR in ESCC. Our results demonstrate that DANCR is highly expressed in ESCC, and acts as an oncogene in ESCC both in vitro and in vivo. Through bioinformatics analysis and experimental validation, we revealed that DANCR promotes ESCC progression by sponging miR-3193 and regulating its target gene DDIT3 expression. These findings highlight the critical role of DANCR in the development of ESCC and suggest its potential as a prognostic predictor and drug therapeutic target.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 5","pages":"1324-1338"},"PeriodicalIF":4.5,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606940","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":"The Combination of PARP and Topoisomerase 1 Inhibitors Improves Radiation Therapy for Ewing Sarcoma","authors":"Jia Xie,&nbsp;Marcia M. Mellado-Lagarde,&nbsp;Kaley Blankenship,&nbsp;Debolina Ganguly,&nbsp;Nathaniel R. Twarog,&nbsp;Brandon Bianski,&nbsp;Matthew Kieffer,&nbsp;Stefan Atkinson,&nbsp;Heather Sheppard,&nbsp;Jessica Gartrell,&nbsp;Samuel Cler,&nbsp;Sara M. Federico,&nbsp;Elizabeth A. Stewart,&nbsp;Christopher L. Tinkle,&nbsp;Anang A. Shelat","doi":"10.1111/cas.70042","DOIUrl":"10.1111/cas.70042","url":null,"abstract":"<p>Although primary tumor control rates after surgery and/or radiation therapy (RT) are generally high in patients with Ewing sarcoma (EWS), those with unresectable tumors have failure rates approaching 30% and experience poorer outcomes. Additionally, although metastatic site irradiation is associated with improved survival, dose, and volume effects influence the long-term toxicity risk. Consequently, it is important to identify novel systemic agents to enhance the therapeutic ratio of RT. Given the reported DNA damage response deficits in EWS, we hypothesized that PARP inhibitors (PARPis) would preferentially potentiate radiation relative to standard-of-care (SOC) chemotherapeutics. We investigated primary and recurrent SOC drugs and PARPis with varied trapping potential in combination with radiation in EWS cell lines. At physiologically relevant concentrations, the strong PARP trapper talazoparib (TAL) potentiated radiation to a greater extent than did SOC or other PARPis, although the magnitude of the effect was modest. The radiosensitizing effect of TAL was mediated through the induction of DNA double-strand breaks, rather than through the catalytic inhibition of PARP1. Drug + RT combinations were further tested in vivo by using orthotopic xenograft models of EWS treated with image-guided fractionated radiation. The addition of RT to the combination of TAL plus irinotecan (IRN), a recently evaluated clinical regimen for relapsed pediatric solid tumors, significantly prolonged survival and reduced tumor burden in all EWS-treated mice. This triplet therapy (TAL + IRN + RT) was feasible and yielded responses in several patients with EWS and may represent a useful salvage strategy in recurrent or progressive disease.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1703-1714"},"PeriodicalIF":4.5,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143606942","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":"Impact of Minimal Residual Disease on Early Recurrence of Liver Metastatic Colorectal Cancer","authors":"Mampei Kawashima,&nbsp;Takeshi Yamada,&nbsp;Toshimitsu Miyasaka,&nbsp;Shintaro Kanaka,&nbsp;Sho Kuriyama,&nbsp;Kay Uehara,&nbsp;Akihisa Matsuda,&nbsp;Ryo Ohta,&nbsp;Hiromichi Sonoda,&nbsp;Nobuhiko Taniai,&nbsp;Hiroshi Yoshida","doi":"10.1111/cas.16442","DOIUrl":"10.1111/cas.16442","url":null,"abstract":"<p>For patients with resectable colorectal liver metastases (CRLM), the efficacy of adjuvant chemotherapy remains a subject of debate. Several studies have concluded that postoperative circulating tumor DNA (ctDNA) is a marker of minimal residual disease (MRD) and is a useful prognostic factor in patients with nonmetastatic colorectal cancer. However, few studies have explored its application in cases involving metastases. This was an observational study that included CRLM patients who underwent primary and liver tumor resection. By examining targeted sequencing of 50 genes commonly mutated in CRC, we identified at least one somatic mutation in each patient's metastatic liver tumor. Blood samples were obtained before and 1-month after surgery. Fifty-three patients were included, and recurrence was diagnosed in 39 patients. Of those, 13 patients experienced early relapse. ctDNA was detected in 45 patients before surgery and 11 after. All MRD-positive patients experienced recurrence. Among them, nine had early recurrence. MRD-positive patients had poorer recurrence free survival (RFS, <i>p</i> &lt; 0.0001) and overall survival (OS, <i>p</i> &lt; 0.0005). Nine of 13 patients with early recurrence had MRD; however, two of 40 patients without early recurrence also had MRD (<i>p</i> &lt; 0.0001). Among 42 MRD-negative patients, adjuvant chemotherapy had no impact of RFS (<i>p</i> = 0.84) or OS (<i>p</i> = 0.54). MRD proved valuable in predicting the risk of postoperative recurrence in patients with CRLM, particularly because MRD positivity emerged as a significant risk factor for early recurrence. Furthermore, it appears that adjuvant chemotherapy may not effectively improve the prognosis for MRD-negative patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 5","pages":"1366-1374"},"PeriodicalIF":4.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.16442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587828","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":"Risk Stratification Prediction of Endometrial Cancer Using Microstructural Mapping Based on Time-Dependent Diffusion MRI","authors":"Yu Zhao,&nbsp;Feng Zhao,&nbsp;Meng Cheng,&nbsp;Gang Wang,&nbsp;Dan Wang,&nbsp;Huijuan Yin,&nbsp;Zhixiao Xue,&nbsp;Yule Chen,&nbsp;Zhen Zhao,&nbsp;Hui Ma,&nbsp;Xiaoxiao Zhang,&nbsp;Junping Wang,&nbsp;Fengtan Li","doi":"10.1111/cas.70036","DOIUrl":"10.1111/cas.70036","url":null,"abstract":"<p>Time-dependent diffusion MRI (<i>t</i>_d-dMRI) has potential in characterizing microstructural features; however, its value in imaging endometrioid endometrial adenocarcinoma (EEA) remains uncertain. Patients surgically confirmed with EEA were finally enrolled in our study. The <i>t</i>_d-dMRI data were acquired using pulsed gradient spin echo sequence and oscillating gradient spin echo sequences. The microstructural markers, including cell diameter, intracellular volume fraction (<i>V</i>_in), cellularity, and extracellular diffusivity (<i>D</i>_ex), were fitted with the imaging microstructural parameters using a limited spectrally edited diffusion (IMPULSED) model. The parameters were compared between low- and high-risk groups and between low- and high-proliferation groups. The diagnostic performance was evaluated using receiver-operating characteristic curve and logistic regression analysis. Diameter, <i>D</i>_ex, ADC_PGSE, ADC_N1, and ADC_N2 were significantly low, whereas cellularity, ΔADC1 and ΔADC2 were significantly high in the high-risk and high-proliferation groups. Cellularity, ΔADC1, and ΔADC2 demonstrated excellent diagnostic efficacy in predicting both risk stratification and proliferation status. Cellularity was the only independent predictor for risk stratification, which exhibited a satisfactory positive correlation with cell density in histopathologic examination. The diagnostic potential of <i>t</i>_d-dMRI-based microstructural mapping was demonstrated to noninvasively probe the pathologic characteristics of patients with EEA in a clinical setting, which provided a valuable contribution to surgical guidance.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1627-1637"},"PeriodicalIF":4.5,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143587831","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":"ATR Inhibition Synergizes With Alkylating PI Polyamide Targeting MYCN by Suppressing DNA Repair in MYCN-Amplified Neuroblastoma","authors":"Xiaoyi Lai,&nbsp;Hiroyuki Yoda,&nbsp;Yuming Qiao,&nbsp;Yuki Kida,&nbsp;Keizo Takenaga,&nbsp;Yoshinao Shinozaki,&nbsp;Nobuko Koshikawa,&nbsp;Atsushi Takatori","doi":"10.1111/cas.70043","DOIUrl":"10.1111/cas.70043","url":null,"abstract":"<p>Amplification of <i>MYCN</i> is a major oncogenic driver of high-risk neuroblastomas. We previously developed CCC-002, a <i>MYCN</i>-selective pyrrole-imidazole polyamide conjugated to a DNA alkylating agent. Administration of CCC-002 to <i>MYCN</i>-amplified (<i>MYCN</i>-amp) neuroblastoma cells triggered the activation of DNA damage responses. Here, we demonstrated that among the DNA damage response inhibitors, ataxia telangiectasia and Rad3-related (ATR) inhibitors synergized with CCC-002 to suppress DNA repair-related genes and induce apoptosis in <i>MYCN</i>-amp neuroblastoma cells. A synergistic antitumor effect was verified in an SK-N-BE(2) xenograft mouse model, in which the combined use of CCC-002 and ATR inhibitor at low doses significantly inhibited tumor progression. Notably, SK-N-BE(2) and SK-N-DZ cells, which showed ATM activation after CCC-002 treatment, exhibited high sensitivity to the combined treatment of ATR inhibitors. Comprehensive analysis of the gene expression profiles revealed that the combination treatment upregulated apoptosis-related pathways and downregulated DNA repair-related pathways. After the combined treatment of CCC-002 and ATR inhibitor, <i>MYCN</i>-amp cells showed less FISH probe signal and mRNA expression of <i>MYCN</i>, which was accompanied by an increase in DNA damage markers in the genomic region of <i>MYCN</i>, highlighting that ATR inhibitors synergize with CCC-002 and play a crucial role in the development of a novel MYCN-targeting therapy for <i>MYCN</i>-amp neuroblastoma.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1691-1702"},"PeriodicalIF":4.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143574429","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}