NeoplasiaPub Date : 2024-11-14DOI: 10.1016/j.neo.2024.101083
Lisa Staffeldt , Hanna Maar , Julia Beimdiek , Samuel Chambers , Kristoffer Riecken , Mark von Itzstein , Falk F.R. Buettner , Arun Everest-Dass , Tobias Lange
{"title":"Depletion of β1,6-N-acetylglucosaminyltransferase reduces E-selectin binding capacity and migratory potential of human gastrointestinal adenocarcinoma cells","authors":"Lisa Staffeldt , Hanna Maar , Julia Beimdiek , Samuel Chambers , Kristoffer Riecken , Mark von Itzstein , Falk F.R. Buettner , Arun Everest-Dass , Tobias Lange","doi":"10.1016/j.neo.2024.101083","DOIUrl":"10.1016/j.neo.2024.101083","url":null,"abstract":"<div><div>The commonly altered glycosylation of tumor cells is a hallmark of tumor progression and metastasis formation. One prominent example is the interaction of sialylated glycans at the tumor cell surface with endothelial (E)-selectin as an early event of an adhesion cascade that enables extravasation of circulating tumor cells (CTCs) into distant tissues. In a previous study, we identified GCNT3 (mucin-type core2/ core4 β1,6-<em>N</em>-acetylglucosaminyltransferase) highly over-expressed in gastrointestinal adenocarcinoma cells that facilitate the canonical E-selectin ligands sialyl-Lewis A and X (sLeA/X) for E-selectin binding and endothelial adhesion. Here we show that shRNA-mediated, stable depletion of GCNT3 reduced sLeA (tumor marker CA19-9) presentation on two out of three tested human gastrointestinal adenocarcinoma cell lines, concurrently showing reduced static E-selectin binding. Significant effects of GCNT3 depletion on dynamic, shear-resistant tumor cell adhesion on immobilized E-selectin as well as endothelial cells were only partially and inconsistently observable as were effects on tumor cell proliferation (2D) or 3D colony formation. Nevertheless, tumor cell migration was consistently reduced upon GCNT3 depletion in all tested cell lines. Detailed glycome analyses revealed that GCNT3 depletion caused cell line-specific alterations in <em>N</em>- and <em>O</em>-glycans as well as glycosphingolipids, collectively mainly associating with decreased Core-2 structures resulting in varied abundance of sialylation and Lewis antigen with consistent phenotypic changes. Distinctive <em>N</em>- and <em>O</em>-glycosylation features were found to be inherent to specific cell types. These findings suggest GCNT3 products as possible carriers of sLeA and static E-selectin binding sites as well as common pro-migratory glycans in human gastrointestinal cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101083"},"PeriodicalIF":4.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639943","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}
NeoplasiaPub Date : 2024-11-14DOI: 10.1016/j.neo.2024.101070
Song Han , Gerik W. Tushoski-Alemán , Peiyi Zhang , Guangrong Zheng , Daohong Zhou , Zhiguang Huo , Jonathan Licht , Thomas J. George , Carmen Allegra , Jose G. Trevino , Steven J. Hughes
{"title":"A novel regimen for pancreatic ductal adenocarcinoma targeting MEK, BCL-xL, and EGFR","authors":"Song Han , Gerik W. Tushoski-Alemán , Peiyi Zhang , Guangrong Zheng , Daohong Zhou , Zhiguang Huo , Jonathan Licht , Thomas J. George , Carmen Allegra , Jose G. Trevino , Steven J. Hughes","doi":"10.1016/j.neo.2024.101070","DOIUrl":"10.1016/j.neo.2024.101070","url":null,"abstract":"<div><div>Oncogenic KRAS signaling plays a critical role in pancreatic ductal adenocarcinoma (PDAC) biology. Recent studies indicate that the combination of MEK and BCL-xL inhibition is synthetically lethal and holds promise for some types of solid cancers, however, patient response was poorly observed in PDAC predominantly due to amplified EGFR signaling. Here, we leverage the advantage of the combinational treatment strategy and designed a triplet regimen targeting the comprehensive RAS activation networks through simultaneously blocking MEK/BCL-xL/EGFR. The cytotoxicity of trametinib (MEK inhibitor), DT2216 (BCL-xL degrader) and afatinib (pan-EGFR inhibitor) and their combination was tested in patient-derived, primary PDAC cells using a live cell imaging system. Patient-derived xenograft (PDX) model was employed for the evaluation of the therapeutic efficacy and safety of the combinational regimen. Targeted pathway cascades activities were analyzed using multiplex phosphor-immune assays. <em>In vitro</em> comparisons showed the addition of afatinib as a third agent was statistically superior compared to a doublet of trametinib+DT2216 in suppressing cell growth and inducing cell death in all cell lines tested. This triplet similarly demonstrated significant superiority over the doublet of MEK/BCL-xL inhibition in the <em>in vivo</em> murine model. The triplet regimen was well tolerated <em>in viv</em>o. Overall tumor growth rates were significantly reduced in doublet treatment compared to controls, and further reduced in the triplet treatment group. Pathway analysis revealed the addition of afatinib in triplet regimen further inhibited PI3K/AKT effectors of p90RSK, p70S6K, and GSK3α/β along with a secondary pathway of P38 MAPK. Our study identifies an important contribution of EGFR inhibition to elevate the response of PDAC, supporting a clinical assessment of this triplet combination in patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101070"},"PeriodicalIF":4.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631073","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}
NeoplasiaPub Date : 2024-11-09DOI: 10.1016/j.neo.2024.101082
Runhui Lu , Yafan Zhang , Ran Chen , Lian Li , Caihu Huang , Zihan Zhou , Yingting Cao , Hongyan Li , Junya Li , Yixin Zhang , Yanli Wang , Jian Huang , Xian Zhao , Jing Feng , Jianxiu Yu , Chunling Du
{"title":"A novel regulatory axis of MSI2-AGO2/miR-30a-3p-CGRRF1 drives cancer chemoresistance by upregulating the KRAS/ERK pathway","authors":"Runhui Lu , Yafan Zhang , Ran Chen , Lian Li , Caihu Huang , Zihan Zhou , Yingting Cao , Hongyan Li , Junya Li , Yixin Zhang , Yanli Wang , Jian Huang , Xian Zhao , Jing Feng , Jianxiu Yu , Chunling Du","doi":"10.1016/j.neo.2024.101082","DOIUrl":"10.1016/j.neo.2024.101082","url":null,"abstract":"<div><div>The KRAS/ERK pathway is crucial in cancer progression and chemotherapy resistance, yet its upstream regulatory mechanism remains elusive. We identified MSI2 as a new promoter of chemotherapy resistance in cancers. MSI2 directly binds to a specific class of mature miRNAs by recognizing the 'UAG' motif and interacts with the essential effector AGO2, highlighting MSI2 as a novel regulatory factor within the miRNA pathway. Specifically, MSI2 recruits UAG-miRNA miR-30a-3p to facilitate its loading onto AGO2, efficiently inhibiting the expression of CGRRF1. Further analysis reveals that CGRRF1 functions as a new ubiquitin E3 ligase for KRAS, mediating the ubiquitination and proteasome degradation of KRAS. Consequently, a novel regulatory axis involving MSI2-AGO2/miR-30a-3p-CGRRF1 positively regulates the KRAS/ERK pathway. Remarkably, platinum-based chemotherapy drugs significantly enhance the levels of phosphorylated ERK1/2 (p-ERK1/2) in cancer cells, and the EGFR inhibitor Gefitinib also increases p-ERK1/2 levels in Gefitinib-resistant cancer cells. Combining small-molecule inhibitors targeting MSI2, such as Ro 08-2750, efficiently alleviated chemoresistance in tumor cells exposed to Platinum and Gefitinib. These findings suggest that MSI2 could be a novel therapeutic target for developing strategies to counteract cancer resistance to treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101082"},"PeriodicalIF":4.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631076","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}
NeoplasiaPub Date : 2024-11-08DOI: 10.1016/j.neo.2024.101078
Alexandre Gries , Karthiga Santhana Kumar , Fabien Kuttler , Özgün Özalp , Veronica Akle , Hanqing Zhang , Michael A. Grotzer , Stephan C.F. Neuhauss , Amin Allalou , Martin Baumgartner
{"title":"Aurora kinase B is required for growth and expansion of medulloblastoma cells in the tissue context","authors":"Alexandre Gries , Karthiga Santhana Kumar , Fabien Kuttler , Özgün Özalp , Veronica Akle , Hanqing Zhang , Michael A. Grotzer , Stephan C.F. Neuhauss , Amin Allalou , Martin Baumgartner","doi":"10.1016/j.neo.2024.101078","DOIUrl":"10.1016/j.neo.2024.101078","url":null,"abstract":"<div><div>The impact of the tissue context on tumor growth and drug response in medulloblastoma (MB) is poorly understood. To gain insights into the growth and dissemination behavior of the MB tumor cells under treatment, we combined three-dimensional cell culture screening with <em>ex vivo</em> organotypic cerebellum slice co-culture (OCSC), which allowed the assessment of tumor cell behavior in the tissue context.</div><div>To identify druggable kinase pathways involved in invasion, we screened a panel of 274 kinase inhibitors and identified aurora kinase B (AURKB) as a potential anti-invasion drug target in MB. We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) Barasertib (AZD1152-HQPA) and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, and Grp3 MB. Importantly, AURKBi are tumor suppressive in the tissue context, also in MB tumor cells that are <em>in vitro</em> resistant to the same treatment. We confirmed the requirement of AURKB for tumor growth and expansion in the tissue context through genetic suppression of AURKB by siRNA. We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor Dasatinib acts synergistically to repress tumor growth and expansion in the highly invasive MB cell model ONS-76, but not in Grp3 MB cells. We demonstrate that tumor growth in the tissue context is suppressed by pharmacological inhibition of AURKB, comparable to the growth reduction observed after X-ray irradiation, which was used as the positive control. Finally, we show that exposure to µM concentrations of Barasertib does not cause developmental toxicity in fish larvae.</div><div>In conclusion, we demonstrate that AURKB is essential for MB tumor growth and expansion in the tissue context and the inhibition of AURKB is equally efficient as irradiation in repressing tumor cell growth. In patients younger than three years, pharmacological targeting of AURKB may thus constitute a novel means to overcome radiotherapy limitations.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101078"},"PeriodicalIF":4.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607010","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":"Cancer incidence and mortality among patients with new-onset atrial fibrillation: A population-based matched cohort study","authors":"Nadine Zakkak , Matthew Barclay , Arturo Gonzalez-Izquierdo , Amand Floriaan Schmidt , Gregory Y.H. Lip , Georgios Lyratzopoulos , Rui Providencia","doi":"10.1016/j.neo.2024.101080","DOIUrl":"10.1016/j.neo.2024.101080","url":null,"abstract":"<div><h3>Background</h3><div>Understanding the risk of cancer after the diagnosis of another condition can present opportunities for earlier diagnosis. We examined the risk of cancer diagnosis conditional on prior diagnosis of atrial fibrillation (AF).</div></div><div><h3>Methods</h3><div>Linked electronic health records were used to identify patients aged ≥18 with new-onset AF and age-sex-matched controls. Cumulative incidence of and mortality from cancer (overall and cancer-site specific) within three months, three months to five years and beyond five years from diagnosis of AF were examined. Findings were further validated using Mendelian randomisation (MR).</div></div><div><h3>Results</h3><div>The cohort included 117,173 patients with new-onset AF and 117,173 matched controls (median age 78). In the first three months, 2.2% of AF patients were diagnosed with cancer vs. 0.47% in controls (relative risk: 4.7 [95%CI 4.2-5.4] in men and 4.4 [95%CI 3.8-5.0] in women). Nearly 80% of cancers related to thoracic or abdominal organs. Differences in cumulative incidence were only evident in women between three months and five years (subdistribution hazard ratio=1.1 [95%CI 1.01-1.12]) and absent in all patients beyond five years. MR analysis did not support the presence of a causal association between AF and major cancer subtypes.</div></div><div><h3>Conclusion</h3><div>There is a large short-term increase in cancer incidence and mortality following new-onset AF. The findings may reflect incidental identification of AF or paraneoplastic manifestation. New-onset AF confers high short-term risk of cancer diagnosis, at levels comparable with symptomatic risk threshold mandating urgent assessment for suspected cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"59 ","pages":"Article 101080"},"PeriodicalIF":4.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607013","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}
NeoplasiaPub Date : 2024-10-30DOI: 10.1016/j.neo.2024.101076
Marco Cordani , Federica Michetti , Ali Zarrabi , Atefeh Zarepour , Cristiano Rumio , Raffaele Strippoli , Fabrizio Marcucci
{"title":"The role of glycolysis in tumorigenesis: From biological aspects to therapeutic opportunities","authors":"Marco Cordani , Federica Michetti , Ali Zarrabi , Atefeh Zarepour , Cristiano Rumio , Raffaele Strippoli , Fabrizio Marcucci","doi":"10.1016/j.neo.2024.101076","DOIUrl":"10.1016/j.neo.2024.101076","url":null,"abstract":"<div><div>Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as “moonlighting” functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101076"},"PeriodicalIF":4.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548448","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}
NeoplasiaPub Date : 2024-10-29DOI: 10.1016/j.neo.2024.101079
Jolanta Guz , Ewelina Zarakowska , Pawel Mijewski , Aleksandra Wasilow , Fabian Lesniewski , Marek Foksinski , Bartosz Brzoszczyk , Piotr Jarzemski , Daniel Gackowski , Ryszard Olinski
{"title":"Epigenetic DNA modifications and vitamin C in prostate cancer and benign prostatic hyperplasia: Exploring similarities, disparities, and pathogenic implications","authors":"Jolanta Guz , Ewelina Zarakowska , Pawel Mijewski , Aleksandra Wasilow , Fabian Lesniewski , Marek Foksinski , Bartosz Brzoszczyk , Piotr Jarzemski , Daniel Gackowski , Ryszard Olinski","doi":"10.1016/j.neo.2024.101079","DOIUrl":"10.1016/j.neo.2024.101079","url":null,"abstract":"<div><h3>Objectives</h3><div>Benign Prostatic Hyperplasia (BPH) and Prostate Cancer (PC) are very common pathologies among aging men. Both disorders involve aberrant cell division and differentiation within the prostate gland. However, the direct link between these two disorders still remains controversial. A plethora of works have demonstrated that inflammation is a major causative factor in both pathologies. Another key factor involved in PC development is DNA methylation and hydroxymethylation.</div></div><div><h3>Methods</h3><div>A broad spectrum of parameters, including epigenetic DNA modifications and 8-oxo-7,8-dihydro-2′-deoxyguanosine, was analyzed by two-dimensional ultraperformance liquid chromatography with tandem mass spectrometry in tissues of BPH, PC, and marginal one, as well as in leukocytes of the patients and the control group. In the same material, the expression of <em>TETs</em> and <em>TDG</em> genes was measured using RT-qPCR. Additionally, vitamin C was quantified in the blood plasma and within cells (leukocytes and prostate tissues).</div></div><div><h3>Results</h3><div>Unique patterns of DNA modifications and intracellular vitamin C (iVC) in BPH and PC tissues, as well as in leukocytes, were found in comparison with control samples. The majority of the alterations were more pronounced in leukocytes than in the prostate tissues.</div></div><div><h3>Conclusions</h3><div>Characteristic DNA methylation/hydroxymethylation and iVC profiles have been observed in both PC and BPH, suggesting potential shared molecular pathways between the two conditions. As a fraction of leukocytes may be recruited to the pathological tissues and can migrate back into the circulation/blood, the observed alterations in leukocytes may reflect dynamic changes associated with the PC development, suggesting their potential utility as early markers of prostate cancer development.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101079"},"PeriodicalIF":4.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548447","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}
NeoplasiaPub Date : 2024-10-24DOI: 10.1016/j.neo.2024.101072
Ran Ran , Martin Trapecar , Douglas K. Brubaker
{"title":"Systematic analysis of human colorectal cancer scRNA-seq revealed limited pro-tumoral IL-17 production potential in gamma delta T cells","authors":"Ran Ran , Martin Trapecar , Douglas K. Brubaker","doi":"10.1016/j.neo.2024.101072","DOIUrl":"10.1016/j.neo.2024.101072","url":null,"abstract":"<div><div>Gamma delta T cells play a crucial role in anti-tumor immunity due to their cytotoxic properties. However, the role and extent of γδ T cells in production of pro-tumorigenic interleukin-17 (IL-17) within the tumor microenvironment of colorectal cancer (CRC) remains controversial. In this study, we re-analyzed nine published human CRC whole-tissue single-cell RNA sequencing datasets, identifying 18,483 γδ T cells out of 951,785 total cells, in the neoplastic or adjacent normal tissue of 165 human CRC patients. Our results confirm that tumor-infiltrating γδ T cells exhibit high cytotoxicity-related transcription in both tumor and adjacent normal tissues, but critically, none of the γδ T cell clusters showed IL-17 production potential. We also identified various γδ T cell subsets, including poised effector-like T cells, tissue-resident memory T cells, progenitor exhausted-like T cells, and exhausted T cells, and noted an increased expression of cytotoxic molecules in tumor-infiltrating γδ T cells compared to their normal area counterparts. We proposed anti-tumor γδ T effector cells may arise from tissue-resident progenitor cells based on the trajectory analysis. Our work demonstrates that γδ T cells in CRC primarily function as cytotoxic effector cells rather than IL-17 producers, mitigating the concerns about their potential pro-tumorigenic roles in CRC, highlighting the importance of accurately characterizing these cells for cancer immunotherapy research and the unneglectable cross-species discrepancy between the mouse and human immune system in the study of cancer immunology.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101072"},"PeriodicalIF":4.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511015","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}
NeoplasiaPub Date : 2024-10-21DOI: 10.1016/j.neo.2024.101075
Le Hien Giang , Kuo-Sheng Wu , Wei-Chung Lee , Shing-Shung Chu , Anh Duy Do , Man-Hsu Huang , Yu-Ling Lin , Chia-Ling Hsieh , Shian-Ying Sung , Yun Yen , Tai-Tong Wong , Che-Chang Chang
{"title":"RRM2 inhibition alters cell cycle through ATM/Rb/E2F1 pathway in atypical teratoid rhabdoid tumor","authors":"Le Hien Giang , Kuo-Sheng Wu , Wei-Chung Lee , Shing-Shung Chu , Anh Duy Do , Man-Hsu Huang , Yu-Ling Lin , Chia-Ling Hsieh , Shian-Ying Sung , Yun Yen , Tai-Tong Wong , Che-Chang Chang","doi":"10.1016/j.neo.2024.101075","DOIUrl":"10.1016/j.neo.2024.101075","url":null,"abstract":"<div><h3>Background</h3><div>Atypical teratoid rhabdoid tumor (ATRT) is an aggressive brain tumor that mainly affects young children. Our recent study reported a promising therapeutic strategy to trigger DNA damage, impede homologous recombination repair, and induce apoptosis in ATRT cells by targeting ribonucleotide reductase regulatory subunit M2 (RRM2). COH29, an inhibitor of RRM2, effectively reduced tumor growth and prolonged survival in vivo. Herein, we explored the underlying mechanisms controlling these functions to improve the clinical applicability of COH29 in ATRT.</div></div><div><h3>Methods</h3><div>Molecular profiling of ATRT patients and COH29-treated cells was analyzed to identify the specific signaling pathways, followed by validation using a knockdown system, flow cytometry, q-PCR, and western blot.</div></div><div><h3>Results</h3><div>Elevated E2F1 and its signaling pathway were correlated with poor prognosis. RRM2 inhibition induced DNA damage and activated ATM, which reduced Rb phosphorylation to promote Rb-E2F1 interaction and hindered E2F1 functions. E2F1 activity suppression led to decreased E2F1-dependent target expressions, causing cell cycle arrest in the G1 phase, decreased S phase cells, and blocked DNA damage repair.</div></div><div><h3>Conclusion</h3><div>Our study highlights the role of ATM/Rb/E2F1 pathway in controlling cell cycle arrest and apoptosis in response to RRM2 inhibition-induced DNA damage. This provides insight into the therapeutic benefits of COH29 and suggests targeting this pathway as a potential treatment for ATRT.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101075"},"PeriodicalIF":4.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511014","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}
NeoplasiaPub Date : 2024-10-19DOI: 10.1016/j.neo.2024.101073
Lan-Lan Pang , Wei-Tao Zhuang , Jun-Jun Li , Bing Li , Yi-Hua Huang , Jun Liao , Meng-Di Li , Li Zhang , Wen-Feng Fang
{"title":"Specifying the choice of EGFR-TKI based on brain metastatic status for advanced NSCLC with EGFR p.L861Q mutation","authors":"Lan-Lan Pang , Wei-Tao Zhuang , Jun-Jun Li , Bing Li , Yi-Hua Huang , Jun Liao , Meng-Di Li , Li Zhang , Wen-Feng Fang","doi":"10.1016/j.neo.2024.101073","DOIUrl":"10.1016/j.neo.2024.101073","url":null,"abstract":"<div><h3>Background</h3><div>In-depth insight into the genomic features of the uncommon EGFR p.L861Q mutant NSCLC is scarcely performed, and no consensus on the preferred treatment strategy has been established. Moreover, the therapeutic implications of EGFR-TKI stratified by clinical and molecular features remained largely unknown.</div></div><div><h3>Methods</h3><div>A multi-center NGS database comprising 44,993 NSCLC samples was utilized for the genomic landscape profiling of EGFR p.L861Q mutation. Furthermore, a real-world cohort of 207 patients harboring EGFR p.L861Q mutation with complete treatment history was curated for comprehensive clinical analysis.</div></div><div><h3>Results</h3><div>L861Q is prevalent in approximately 2.1% of EGFR-mutated NSCLC and is typically co-mutated with EGFR p.G719X on the same allele (20%) and exhibits co-occurrent EGFR copy number amplification in approximately 17% of cases. In the first-line setting, afatinib and third-generation EGFR-TKI have been shown to yield notably superior treatment outcomes compared to first-generation EGFR-TKI (1<sup>st</sup> vs.2<sup>nd</sup> vs.3<sup>rd</sup> generations, ORR: 15.8% vs.56.5% vs.46.7%, <em>P</em>=0.01; median PFS: 6.4 vs.13.5 vs.15.1 months, <em>P</em>=0.002). This finding consistently held for patients without CNS metastases (1<sup>st</sup> vs.2<sup>nd</sup> vs.3<sup>rd</sup> generations, median PFS:6.0 vs.18.2 vs.14.1 months, <em>P</em>=0.003). In contrast, third-generation EGFR-TKI demonstrated superior efficacy compared to afatinib or first-generation TKI among the subgroup of brain metastasis (Pooled 1<sup>st</sup>/2<sup>nd</sup>-generation vs.3<sup>rd</sup>-generation TKI, brain ORR:0.00% vs.33.33%; median PFS:7.9 vs.19.3 months, <em>P</em>=0.021). Additional concurrent EGFR mutations or EGFR amplification did not yield a discernible impact on the efficacy of EGFR-TKI.</div></div><div><h3>Conclusions</h3><div>The present study comprehensively elucidates the molecular features of EGFR p.L861Q mutation and underscores the optimal therapeutic choice of first-line EGFR-TKI based on brain metastatic status.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"58 ","pages":"Article 101073"},"PeriodicalIF":4.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478275","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}