NAR cancer最新文献_第3页

Identification of siRNA silencing TGFβ1 and VEGFR2 and utility of the combination in targeting immune modulation and angiogenesis in treating melanoma in vivo. siRNA沉默tgf - β1和VEGFR2的鉴定及其在靶向免疫调节和血管生成治疗黑色素瘤中的应用

IF 4.6

NAR cancer Pub Date : 2026-01-19 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcag002

Deling Wang, Wanying Jia, Jinping Lian, Jin Zhang, Xiangyu Ren, Zhiyuan Wang, Weihui Liu, Cheng Zhou, Jun Xu, Weiwei Tian, Patrick Y Lu, David M Evans

{"title":"Identification of siRNA silencing TGFβ1 and VEGFR2 and utility of the combination in targeting immune modulation and angiogenesis in treating melanoma in vivo.","authors":"Deling Wang, Wanying Jia, Jinping Lian, Jin Zhang, Xiangyu Ren, Zhiyuan Wang, Weihui Liu, Cheng Zhou, Jun Xu, Weiwei Tian, Patrick Y Lu, David M Evans","doi":"10.1093/narcan/zcag002","DOIUrl":"10.1093/narcan/zcag002","url":null,"abstract":"Late-stage melanoma can metastasize to organs beyond the skin, such as lungs, liver, brain, and bone, resulting in reduced patient survival time. The incidence of melanoma is currently growing worldwide, and novel therapeutic options are needed to prevent its dissemination and to improve therapeutic results. This paper describes the use of small interfering RNA (siRNA) to silence expression of TGFβ1 and VEGFR2 as an alternative approach for melanoma treatment. These two therapeutic targets have been well-documented in tumor immune modulation and tumor angiogenesis within the tumor microenvironment (TME). Two potent siRNA candidates targeting TGFβ1 or VEGFR2 were identified with 100% identity to sequences of mouse, non-human primate (NHP), and humans. The combination of the two siRNAs was formulated with a clinically validated polypeptide nanoparticle (PNP) carrier. This PNP-packaged siRNA formulation, STP355, administered intravenously in mice bearing syngeneic melanoma tumors, demonstrated silencing of both targets and a reduction in tumor growth. STP355 also reduced tumor weight significantly, without the toxicity observed with cisplatin, resulting in prolonged survival of mice compared with this small molecule. It increased immune cell penetration into TME and reduced metastases to the lung. STP355 was more efficacious than, and somewhat additive with, immune checkpoint inhibitory monoclonal antibodies.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 1","pages":"zcag002"},"PeriodicalIF":4.6,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12813501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146014042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ribosome biogenesis is increased in hepatocellular carcinoma and represents a potential therapeutic target. 核糖体生物发生在肝细胞癌中增加，代表了一个潜在的治疗靶点。

IF 4.6

NAR cancer Pub Date : 2026-01-16 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcaf058

Sille Blangstrup Geisler, Kezia Catharina Oxe, Stavroula Boukoura, Ekaterina Dulina, Dorthe Helena Larsen

{"title":"Ribosome biogenesis is increased in hepatocellular carcinoma and represents a potential therapeutic target.","authors":"Sille Blangstrup Geisler, Kezia Catharina Oxe, Stavroula Boukoura, Ekaterina Dulina, Dorthe Helena Larsen","doi":"10.1093/narcan/zcaf058","DOIUrl":"10.1093/narcan/zcaf058","url":null,"abstract":"Globally, liver cancer is the sixth most prevalent cancer type and the third leading cause of cancer-related deaths, making the need for improved treatment evident. We conducted a pan-cancer tissue microarray analysis to identify cancer types with upregulated ribosome biogenesis, potentially suitable for treatment with nucleolar-targeting compounds. Our screening identified liver cancer as a potential candidate. Gene expression analysis confirmed upregulation of nucleolar factors facilitating ribosome biogenesis that correlated with poor prognosis. In hepatocellular carcinoma (HCC) cell lines, constituting around 80% of liver cancer cases, we confirmed the upregulation of the nucleolar proteins Treacle, UBF, and Fibrillarin, involved in transcription and processing of ribosomal RNA (rRNA). Measurements of rRNA also confirmed increased nucleolar activity. We treated the HCC cell lines with nucleolar-targeting compounds and observed increased sensitivity in the HCC cell lines. Notably, nucleolar targeting compounds demonstrated a broader therapeutic window than that observed for Sorafenib, a clinically approved targeted therapy. Furthermore, we investigated how nucleolar factors change during HCC stages and found a progressive increase in Treacle and Fibrillarin in advanced stages of HCC. Our results demonstrate aberrant nucleolar activity in HCC and propose targeting ribosome biogenesis as a therapeutic strategy to improve HCC patient outcomes.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 1","pages":"zcaf058"},"PeriodicalIF":4.6,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12809584/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeted CRISPR knockout screening identifies known and novel chemogenomic interactions between DNA damaging agents and DNA repair genes. 靶向CRISPR敲除筛选鉴定DNA损伤剂和DNA修复基因之间已知和新的化学基因组相互作用。

IF 4.6

NAR cancer Pub Date : 2026-01-09 eCollection Date: 2026-03-01 DOI: 10.1093/narcan/zcaf052

Collin D Heer, James L Elia, Vijay Menon, Spenser S Johnson, Sofia R Arbelaez, Sam Friedman, Francesc Lopez-Giraldez, Ranjini K Sundaram, Seth B Herzon, Ranjit S Bindra, Susan E Gueble

{"title":"Targeted CRISPR knockout screening identifies known and novel chemogenomic interactions between DNA damaging agents and DNA repair genes.","authors":"Collin D Heer, James L Elia, Vijay Menon, Spenser S Johnson, Sofia R Arbelaez, Sam Friedman, Francesc Lopez-Giraldez, Ranjini K Sundaram, Seth B Herzon, Ranjit S Bindra, Susan E Gueble","doi":"10.1093/narcan/zcaf052","DOIUrl":"10.1093/narcan/zcaf052","url":null,"abstract":"Genetic instability is a hallmark of cancer, often arising from mutations to DNA damage repair and response (DDR) genes. Classical genetic, biochemical, and structural approaches elucidated the foundational mechanisms of DDR pathways and provided a scientific understanding of their involvement in repair of lesions induced by broad classes of DNA-damaging agents (DDAs). However, given the chemical diversity of DDAs and resultant DNA lesions, along with the multitude of interconnected DDR factors, the chemogenomic landscape of DDA-DDR interactions remains incompletely mapped. To this end, we developed a DDR-targeted, CRISPR knockout screening approach and assessed relationships amongst 353 DNA repair genes and 15 DDAs in LN229 glioma cells. Within this dataset of 5295 DDR-related chemogenomic interactions, we identified many established interactions and discovered novel ones. For example, we observed a specific role of transcription-coupled nucleotide excision repair in the repair of adducts generated by monofunctional alkylating agents, a role for the Fanconi anemia pathway in addressing methyl lesions, overt differences in DSB repair following treatment with topoisomerase I versus II poisons, and repair dependencies associated with the imidazotetrazines temozolomide, mitozolomide, and KL-50. Future directions will continue to investigate the mechanisms of novel chemogenomic interactions that we have uncovered as well as work to identify chemogenomic interactions amenable to clinical translation.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"8 1","pages":"zcaf052"},"PeriodicalIF":4.6,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12783042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145954595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Replication-associated base excision repair/single-strand break repair regulates PARG inhibitor response via the PRMT1/PRMT5/ATR axis. 复制相关的碱基切除修复/单链断裂修复通过PRMT1/PRMT5/ATR轴调节PARG抑制剂的反应。

IF 4.6

NAR cancer Pub Date : 2025-12-31 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf057

Md Ibrahim, Wynand P Roos, Jacob C Schwartz, Md Maruf Khan, Rasha Q Al-Rahahleh, Libby A Beers, Charlotte R Pearson, Kahrie T Langham, Louis Boyang, Jennifer Clark, Faisal Hayat, Qingming Fang, Christopher A Koczor, Marie E Migaud, Robert W Sobol

{"title":"Replication-associated base excision repair/single-strand break repair regulates PARG inhibitor response via the PRMT1/PRMT5/ATR axis.","authors":"Md Ibrahim, Wynand P Roos, Jacob C Schwartz, Md Maruf Khan, Rasha Q Al-Rahahleh, Libby A Beers, Charlotte R Pearson, Kahrie T Langham, Louis Boyang, Jennifer Clark, Faisal Hayat, Qingming Fang, Christopher A Koczor, Marie E Migaud, Robert W Sobol","doi":"10.1093/narcan/zcaf057","DOIUrl":"10.1093/narcan/zcaf057","url":null,"abstract":"Poly(ADP-ribose) polymerases 1 and 2 (PARP1/PARP2), and poly(ADP-ribose) glycohydrolase (PARG), modulate the level of poly(ADP-ribose) (PAR), a post-translational protein modification, in response to DNA damage or replication stress. Here, we find that replication-dependent and PARP1/PARP2-mediated PARylation recruits the base excision repair (BER)/single-strand break repair (SSBR) scaffold protein XRCC1 and the associated factors DNA polymerase β (POLB), aprataxin (APTX), and DNA ligase isoform 3 (LIG3). Further, these BER/SSBR proteins promote resistance to inhibitors of PARP1/PARP2 and PARG, as loss of these proteins sensitizes glioblastoma and ovarian cancer cells to each. In addition, depletion of these replication-associated BER/SSBR factors leads to enhanced PAR levels and PARG inhibitor-induced activation of the ATR/CHK1 S-phase checkpoint kinases. Both PARG inhibition and ATR inhibition lead to elevated ATM- and DNA-PK-dependent KAP1 phosphorylation. In turn, inhibition of either ATR or CHK1 enhances the cellular response to PARG inhibitors. Finally, inhibition of the ATR regulators PRMT1 or PRMT5 synergizes with PARG inhibition, implicating replication-associated BER/SSBR and PARylation in the activation of the PRMT1/PRMT5/ATR axis. This study highlights the role of BER/SSBR in protecting the cell during S-phase to suppress PARylation-induced checkpoint activation, which may suggest a potential intervention strategy for PARG inhibitor-resistant tumors.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf057"},"PeriodicalIF":4.6,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12754786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145890889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disruption of protein-protein interaction hotspots in the C-terminal domain of MLH1 confers mismatch repair deficiency. 破坏MLH1 c端结构域的蛋白相互作用热点会导致错配修复缺陷。

IF 4.6

NAR cancer Pub Date : 2025-12-31 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf055

Keri M Fishwick, Diego Gomez Vieito, Giada Greco, Giulio Collotta, Marco Gatti, Anastasija A Kulik, Raphaël Guérois, Ivan Corbeski, Ashutosh S Phadte, Issam Senoussi, Petr Cejka, Anna Pluciennik, Antonio Porro, Alessandro A Sartori

{"title":"Disruption of protein-protein interaction hotspots in the C-terminal domain of MLH1 confers mismatch repair deficiency.","authors":"Keri M Fishwick, Diego Gomez Vieito, Giada Greco, Giulio Collotta, Marco Gatti, Anastasija A Kulik, Raphaël Guérois, Ivan Corbeski, Ashutosh S Phadte, Issam Senoussi, Petr Cejka, Anna Pluciennik, Antonio Porro, Alessandro A Sartori","doi":"10.1093/narcan/zcaf055","DOIUrl":"10.1093/narcan/zcaf055","url":null,"abstract":"MutLα, a heterodimer of MLH1 and PMS2, plays a key role in DNA mismatch repair (MMR), which maintains genomic stability by correcting replication errors. Loss of MLH1 function causes MMR deficiency (MMRd), leading to elevated mutation rates and increased cancer susceptibility. However, MMRd can offer a therapeutic advantage, as high tumour mutational burden enhances the efficacy of immune checkpoint inhibition. MMR also drives somatic expansion of CAG repeats linked to Huntington's disease (HD) pathogenesis. The C-terminal domain (CTD) of MLH1 contains at least two distinct protein-protein interaction (PPI) sites. The S1 site supports heterodimerization with the PMS2 endonuclease, whereas the S2 site interacts with MIP-boxes present in MMR-associated factors (EXO1, MSH3) and in the DNA repair nuclease FAN1. Here, using MLH1-S2 mutant cell models and synthetic FAN1-derived peptides containing two adjacent MLH1-binding motifs (MIP and MIM), we demonstrate that selective disruption of MLH1 PPIs impairs MMR in vitro. We further reveal that the peptide is able to inhibit the latent endonuclease activity of recombinant MutLα, possibly via competing with a putative MIM within PMS2. Our findings define key PPI interfaces within the MLH1(CTD) that govern MMR activity and may offer novel therapeutic opportunities to exploit MMRd in cancer and HD.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf055"},"PeriodicalIF":4.6,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12754775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145890898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Uracil-DNA glycosylase deficiency is associated with repressed tumor cell-intrinsic inflammatory signaling and altered sensitivity to exogenous interferons. 尿嘧啶- dna糖基酶缺乏与肿瘤细胞内在炎症信号的抑制和对外源性干扰素的敏感性改变有关。

IF 4.6

NAR cancer Pub Date : 2025-12-31 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf054

Frank P Vendetti, Pinakin Pandya, Carina R Sclafani, Sudipta Pathak, Raquel Buj, Reyna E Jones, Daniel Ivanov, Katherine M Aird, Robert W Sobol, Christopher J Bakkenist

{"title":"Uracil-DNA glycosylase deficiency is associated with repressed tumor cell-intrinsic inflammatory signaling and altered sensitivity to exogenous interferons.","authors":"Frank P Vendetti, Pinakin Pandya, Carina R Sclafani, Sudipta Pathak, Raquel Buj, Reyna E Jones, Daniel Ivanov, Katherine M Aird, Robert W Sobol, Christopher J Bakkenist","doi":"10.1093/narcan/zcaf054","DOIUrl":"10.1093/narcan/zcaf054","url":null,"abstract":"2'-deoxyuridine (dU) is a common DNA lesion resulting from cytosine deamination and from dUMP incorporation by DNA polymerases, both of which are prevalent in cancer. The primary mechanism that repairs dU lesions in genomic DNA is base excision repair initiated by Uracil-DNA Glycosylase 2 (UNG2). We generated Ung knockout mouse B16 melanoma cells to investigate the consequences of UNG deficiency in a well-characterized, immunocompetent, syngeneic mouse cancer model. We show that UNG-deficient (ΔUNG) B16 tumors exhibited T cell-dependent, delayed growth in vivo and were more responsive to anti-PD-L1 therapy. Immune profiling revealed reduced CD8+ T cell infiltration but augmented IFN-γ-competent effector CD4+ T cells in ΔUNG tumors. In vitro, ΔUNG tumor cells exhibited strongly suppressed cell-intrinsic type-I interferon, type-II interferon, and inflammatory signaling gene expression signatures as well as altered cytokine and chemokine secretion. In vivo, ΔUNG tumors exhibited a modified inflammatory cytokine and chemokine milieu. Furthermore, ΔUNG tumor cells had altered sensitivity to exogenous interferons in vitro, with increased sensitivity to IFN-γ but decreased sensitivity to IFN-α/β. Collectively, our data show that tumor-cell-specific UNG deficiency results in an altered tumor microenvironment in vivo and provide proof of concept for the use of UNG inhibitors to modulate inflammatory pathways in tumors.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf054"},"PeriodicalIF":4.6,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12754777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145890812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IGF1R-targeted delivery of a bridged nucleic acid oligonucleotide-peptide conjugate for microRNA-21 inhibition in triple-negative breast cancer. igf1r靶向递送桥接核酸寡核苷酸-肽偶联物用于抑制三阴性乳腺癌中的microRNA-21。

IF 4.6

NAR cancer Pub Date : 2025-12-31 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf053

Yuanyuan Jin, Vilas S Desai, Jason D Mazzaroth, Eric Wickstrom

{"title":"IGF1R-targeted delivery of a bridged nucleic acid oligonucleotide-peptide conjugate for microRNA-21 inhibition in triple-negative breast cancer.","authors":"Yuanyuan Jin, Vilas S Desai, Jason D Mazzaroth, Eric Wickstrom","doi":"10.1093/narcan/zcaf053","DOIUrl":"10.1093/narcan/zcaf053","url":null,"abstract":"Triple-negative breast cancer (TNBC), defined by the absence of ER, PR, and Her2, impacts over 46 000 U.S. women annually, disproportionately affecting minority ethnic groups and individuals with BRCA mutations. Despite advancements such as PARP inhibitors, TNBC remains highly aggressive, with frequent recurrences and a 50% mortality rate within four years, underscoring the urgent need for more effective targeted therapies. MicroRNAs (miRNAs) represent a novel therapeutic approach. In TNBC, overexpressed miR-21 drives tumor progression, immune evasion, treatment resistance, and metastasis. Targeted miR-21 inhibition could curb these effects while minimizing harm to normal cells. We developed a peptide-conjugated miR-21 inhibitor targeting TNBC cells via the overexpressed IGF1 receptor (IGF1R), associated with poor prognosis. Using aminomethyl-bridged nucleic acid (BNA) chemistry, a serum-stable anti-miR-21 RNA analog was designed and tested for its effects on TNBC cell proliferation, apoptosis, tumor suppressor expression, and immune checkpoint regulation. Conjugation to an IGF1 peptide analog improved delivery, demonstrating tumor-specific biodistribution, efficacy, and safety in TNBC-bearing mice. The miR-21 inhibitor-peptide conjugate reduced proliferation, induced apoptosis, elevated tumor suppressors, and suppressed immune checkpoints in TNBC cell lines. In vivo, it concentrated in tumors, inhibited tumor growth, and showed no detectable liver or kidney toxicity at the tested dose, supporting therapeutic potential.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf053"},"PeriodicalIF":4.6,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12754785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145890896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The alternative lengthening of telomeres pathway through a DNA repair lens: mechanism and therapeutic opportunities. 通过DNA修复透镜的端粒延长途径：机制和治疗机会。

IF 4.6

NAR cancer Pub Date : 2025-12-31 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf056

Daniela Muoio, Elise Fouquerel

{"title":"The alternative lengthening of telomeres pathway through a DNA repair lens: mechanism and therapeutic opportunities.","authors":"Daniela Muoio, Elise Fouquerel","doi":"10.1093/narcan/zcaf056","DOIUrl":"10.1093/narcan/zcaf056","url":null,"abstract":"The alternative lengthening of telomeres (ALT) pathway is a telomerase-independent telomere maintenance mechanism leveraged by a subset of human cancers. In these tumors, telomere DNA synthesis is achieved via homologous recombination-based mechanisms. ALT-positive tumors harbor distinctive hallmarks, including heterogeneous telomere lengths, the presence of ALT-associated PML bodies, extrachromosomal telomeric repeats, telomere fragility, and mitotic DNA synthesis. These features reflect underlying replication stress and deregulated DNA repair mechanisms. ALT is associated with various tumor types and can often contribute to worsening the patient's prognosis. Strikingly, ALT cancers are particularly enriched in childhood cancers, especially in high-grade gliomas, neuroblastoma, and osteosarcomas, three cancer types that are very common in children. Here, we provide a comprehensive review of the DNA repair factors that drive ALT activation and maintenance and explore emerging therapeutic opportunities associated with the selective dependence of ALT cancer cells on these specific DNA damage response factors. We aim to promote a growing interest in deciphering the DNA-repair-dependent mechanisms of ALT, ultimately helping to build a foundation for the discovery of novel therapeutics against aggressive ALT tumors, for which prognosis is particularly poor and treatments are currently severely lacking.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf056"},"PeriodicalIF":4.6,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12754784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145890865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic approaches for targeted oxidative stress. 靶向氧化应激的遗传方法。

IF 4.6

NAR cancer Pub Date : 2025-12-23 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf049

Aninda Dey, Ryan P Barnes

引用次数: 0

Contrasting roles of APE1 and APE2 in genome maintenance, cancer development, and therapeutic targeting. APE1和APE2在基因组维持、癌症发展和治疗靶向中的作用对比

IF 4.6

NAR cancer Pub Date : 2025-12-23 eCollection Date: 2025-12-01 DOI: 10.1093/narcan/zcaf048

Aman Sharma, Helen E Grimsley, Katharine Courtemanche, Simon N Powell

{"title":"Contrasting roles of APE1 and APE2 in genome maintenance, cancer development, and therapeutic targeting.","authors":"Aman Sharma, Helen E Grimsley, Katharine Courtemanche, Simon N Powell","doi":"10.1093/narcan/zcaf048","DOIUrl":"10.1093/narcan/zcaf048","url":null,"abstract":"Apurinic/apyrimidinic endonucleases - APE1 and APE2 are central to genome maintenance and the cellular DNA damage response, with expanding relevance in cancer biology. APE1 is the primary endonuclease in base excision repair and functions as a redox coactivator of transcription factors. In contrast, APE2 exhibits PCNA dependent 3'-5' exonuclease and 3'-phosphodiesterase activities, contributing to microhomology-mediated end joining, ATR-Chk1 activation, and immunoglobulin diversification. Both enzymes are often deregulated in cancer: APE1 is frequently overexpressed, drives tumor progression and chemoresistance, while APE2 is similarly upregulated in multiple malignancies. APE1 can be targeted by redox-specific or endonuclease inhibitors, with early clinical evidence of biological activity and tolerability. Although APE2-specific inhibitors remain in early development, emerging synthetic lethality data and preclinical studies highlight APE2 as a novel clinical target in breast cancer type 1/2 susceptibility (BRCA)-mutated cancers. This review discusses the structural and functional roles of APE1 and APE2, their contributions to cancer biology and therapeutics, recent advances in inhibitor development, and future strategies for precision oncology.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"7 4","pages":"zcaf048"},"PeriodicalIF":4.6,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12723232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145829456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0