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1دورية أكاديمية
المؤلفون: Bhin, Jinhyuk, Yemelyanenko, Julia, Chao, Xue, Klarenbeek, Sjoerd, Opdam, Mark, Malka, Yuval, Hoekman, Liesbeth, Kruger, Dinja, Bleijerveld, Onno, Brambillasca, Chiara S., Sprengers, Justin, Siteur, Bjørn, Annunziato, Stefano, van Haren, Matthijs J., Martin, Nathaniel I., van de Ven, Marieke, Peters, Dennis, Agami, Reuven, Linn, Sabine C., Boven, Epie, Altelaar, Maarten, Jonkers, Jos, Zingg, Daniel, Wessels, Lodewyk F. A.
المصدر: Bhin , J , Yemelyanenko , J , Chao , X , Klarenbeek , S , Opdam , M , Malka , Y , Hoekman , L , Kruger , D , Bleijerveld , O , Brambillasca , C S , Sprengers , J , Siteur , B , Annunziato , S , van Haren , M J , Martin , N I , van de Ven , M , Peters , D , Agami , R , Linn , S C , Boven , E , Altelaar , M , Jonkers , J , Zingg , D & ....
الوصف: Targeting the PI3K–AKT–mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K–AKT–mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.
الإتاحة: https://doi.org/10.1084/jem.20211743Test
https://research.vumc.nl/en/publications/b09ce808-abc3-4c5d-8838-ad7aa307f2b7Test
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85183403885&origin=inwardTest -
2دورية أكاديمية
المؤلفون: Zingg, Daniel, Bhin, Jinhyuk, Yemelyanenko, Julia, Kas, Sjors M., Rolfs, Frank, Lutz, Catrin, Lee, Jessica K., Klarenbeek, Sjoerd, Silverman, Ian M., Annunziato, Stefano, Chan, Chang S., Piersma, Sander R., Eijkman, Timo, Badoux, Madelon, Gogola, Ewa, Siteur, Bjørn, Sprengers, Justin, de Klein, Bim, de Goeij-de Haas, Richard R., Riedlinger, Gregory M., Ke, Hua, Madison, Russell, Drenth, Anne Paulien, van der Burg, Eline, Schut, Eva, Henneman, Linda, van Miltenburg, Martine H., Proost, Natalie, Zhen, Huiling, Wientjens, Ellen, de Bruijn, Roebi, de Ruiter, Julian R., Boon, Ute, de Korte-Grimmerink, Renske, van Gerwen, Bastiaan, Féliz, Luis, Abou-Alfa, Ghassan K., Ross, Jeffrey S., van de Ven, Marieke, Rottenberg, Sven, Cuppen, Edwin, Chessex, Anne Vaslin, Ali, Siraj M., Burn, Timothy C., Jimenez, Connie R., Ganesan, Shridar, Wessels, Lodewyk F. A., Jonkers, Jos
المصدر: Zingg , D , Bhin , J , Yemelyanenko , J , Kas , S M , Rolfs , F , Lutz , C , Lee , J K , Klarenbeek , S , Silverman , I M , Annunziato , S , Chan , C S , Piersma , S R , Eijkman , T , Badoux , M , Gogola , E , Siteur , B , Sprengers , J , de Klein , B , de Goeij-de Haas , R R , Riedlinger , G M , Ke , H , Madison , R , Drenth ....
الوصف: This paper was originally published under a standard Springer Nature license (
الإتاحة: https://doi.org/10.1038/s41586-022-05287-810.1038/s41586-022-05066-5Test
https://research.vumc.nl/en/publications/eb0a9040-05d4-4551-9c06-c6c93a43f25fTest
http://www.scopus.com/inward/record.url?scp=85137051534&partnerID=8YFLogxKTest -
3دورية أكاديمية
المؤلفون: Zingg, Daniel, Bhin, Jinhyuk, Yemelyanenko, Julia, Kas, Sjors M., Rolfs, Frank, Lutz, Catrin, Lee, Jessica K., Klarenbeek, Sjoerd, Silverman, Ian M., Annunziato, Stefano, Chan, Chang S., Piersma, Sander R., Eijkman, Timo, Badoux, Madelon, Gogola, Ewa, Siteur, Bjørn, Sprengers, Justin, de Klein, Bim, de Goeij-de Haas, Richard R., Riedlinger, Gregory M., Ke, Hua, Madison, Russell, Drenth, Anne Paulien, van der Burg, Eline, Schut, Eva, Henneman, Linda, van Miltenburg, Martine H., Proost, Natalie, Zhen, Huiling, Wientjens, Ellen, de Bruijn, Roebi, de Ruiter, Julian R., Boon, Ute, de Korte-Grimmerink, Renske, van Gerwen, Bastiaan, Féliz, Luis, Abou-Alfa, Ghassan K., Ross, Jeffrey S., van de Ven, Marieke, Rottenberg, Sven, Cuppen, Edwin, Chessex, Anne Vaslin, Ali, Siraj M., Burn, Timothy C., Jimenez, Connie R., Ganesan, Shridar, Wessels, Lodewyk F. A., Jonkers, Jos
المصدر: Zingg , D , Bhin , J , Yemelyanenko , J , Kas , S M , Rolfs , F , Lutz , C , Lee , J K , Klarenbeek , S , Silverman , I M , Annunziato , S , Chan , C S , Piersma , S R , Eijkman , T , Badoux , M , Gogola , E , Siteur , B , Sprengers , J , de Klein , B , de Goeij-de Haas , R R , Riedlinger , G M , Ke , H , Madison , R , Drenth ....
الوصف: Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1–9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1–E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.
الإتاحة: https://doi.org/10.1038/s41586-022-05066-5Test
https://research.vumc.nl/en/publications/2d654cd1-b221-419b-990b-85fac75a1093Test
http://www.scopus.com/inward/record.url?scp=85136216088&partnerID=8YFLogxKTest -
4دورية أكاديمية
المؤلفون: Zingg, Daniel, Bhin, Jinhyuk, Yemelyanenko, Julia, Kas, Sjors M, Rolfs, Frank, Lutz, Catrin, Lee, Jessica K, Klarenbeek, Sjoerd, Silverman, Ian M, Annunziato, Stefano, Chan, Chang S, Piersma, Sander R, Eijkman, Timo, Badoux, Madelon, Gogola, Ewa, Siteur, Bjørn, Sprengers, Justin, de Klein, Bim, de Goeij-de Haas, Richard R, Riedlinger, Gregory M, Ke, Hua, Madison, Russell, Drenth, Anne Paulien, van der Burg, Eline, Schut, Eva, Henneman, Linda, van Miltenburg, Martine H, Proost, Natalie, Zhen, Huiling, Wientjens, Ellen, de Bruijn, Roebi, de Ruiter, Julian R, Boon, Ute, de Korte-Grimmerink, Renske, van Gerwen, Bastiaan, Féliz, Luis, Abou-Alfa, Ghassan K, Ross, Jeffrey S, van de Ven, Marieke, Rottenberg, Sven, Cuppen, Edwin, Chessex, Anne Vaslin, Ali, Siraj M, Burn, Timothy C, Jimenez, Connie R, Ganesan, Shridar, Wessels, Lodewyk F A, Jonkers, Jos
المصدر: Zingg, Daniel; Bhin, Jinhyuk; Yemelyanenko, Julia; Kas, Sjors M; Rolfs, Frank; Lutz, Catrin; Lee, Jessica K; Klarenbeek, Sjoerd; Silverman, Ian M; Annunziato, Stefano; Chan, Chang S; Piersma, Sander R; Eijkman, Timo; Badoux, Madelon; Gogola, Ewa; Siteur, Bjørn; Sprengers, Justin; de Klein, Bim; de Goeij-de Haas, Richard R; Riedlinger, Gregory M; . (2022). Publisher Correction: Truncated FGFR2 is a clinically actionable oncogene in multiple cancers. Nature, 609(7929), E13. Springer Nature 10.1038/s41586-022-05287-8
مصطلحات موضوعية: 630 Agriculture, 610 Medicine & health
وصف الملف: application/pdf
العلاقة: https://boris.unibe.ch/172656Test/
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5دورية أكاديمية
المؤلفون: Ratz, Leonie, Brambillasca, Chiara, Bartke, Leandra, Huetzen, Maxim A., Goergens, Jonas, Leidecker, Orsolya, Jachimowicz, Ron D., van de Ven, Marieke, Proost, Natalie, Siteur, Bjørn, de Korte-Grimmerink, Renske, Bouwman, Peter, Pulver, Emilia M., de Bruijn, Roebi, Isensee, Jörg, Hucho, Tim, Pandey, Gaurav, van Lohuizen, Maarten, Mallmann, Peter, Reinhardt, Hans Christian, Jonkers, Jos, Puppe, Julian
المساهمون: German-Israeli Foundation for Scientific Research and Development, Deutsche Forschungsgemeinschaft, José Carreras Leukämie-Stiftung, Else Kröner-Fresenius-Stiftung, Deutsche Krebshilfe, Bundesministerium für Bildung und Forschung, Universität zu Köln, KWF Kankerbestrijding, Lundbeckfonden, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Universitätsklinikum Köln
المصدر: Breast Cancer Research ; volume 24, issue 1 ; ISSN 1465-542X
الوصف: Background The majority of BRCA1 -mutant breast cancers are characterized by a triple-negative phenotype and a basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options are limited, highlighting the need for the development of novel targeted therapies for this tumor subtype. Methods Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient breast tumors and blocking EZH2 enzymatic activity could be a potent treatment strategy. To validate the role of EZH2 as a therapeutic target and to identify new synergistic drug combinations, we performed a high-throughput drug combination screen in various cell lines derived from BRCA1-deficient and -proficient mouse mammary tumors. Results We identified the combined inhibition of EZH2 and the proximal DNA damage response kinase ATM as a novel synthetic lethality-based therapy for the treatment of BRCA1-deficient breast tumors. We show that the combined treatment with the EZH2 inhibitor GSK126 and the ATM inhibitor AZD1390 led to reduced colony formation, increased genotoxic stress, and apoptosis-mediated cell death in BRCA1-deficient mammary tumor cells in vitro. These findings were corroborated by in vivo experiments showing that simultaneous inhibition of EZH2 and ATM significantly increased anti-tumor activity in mice bearing BRCA1-deficient mammary tumors. Conclusion Taken together, we identified a synthetic lethal interaction between EZH2 and ATM and propose this synergistic interaction as a novel molecular combination for the treatment of BRCA1 -mutant breast cancer.
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6دورية أكاديمية
المؤلفون: Spanjaard, Aldo, Shah, Ronak, de Groot, Daniël, Buoninfante, Olimpia Alessandra, Morris, Ben, Lieftink, Cor, Pritchard, Colin, Zürcher, Lisa M, Ormel, Shirley, Catsman, Joyce J I, de Korte-Grimmerink, Renske, Siteur, Bjørn, Proost, Natalie, Boadum, Terry, van de Ven, Marieke, Song, Ji-Ying, Kreft, Maaike, van den Berk, Paul C M, Beijersbergen, Roderick L, Jacobs, Heinz
المساهمون: Dutch Cancer Foundation, KWF
المصدر: Nucleic Acids Research ; volume 50, issue 13, page 7420-7435 ; ISSN 0305-1048 1362-4962
مصطلحات موضوعية: Genetics
الوصف: Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.
الإتاحة: https://doi.org/10.1093/nar/gkac545Test
https://academic.oup.com/nar/article-pdf/50/13/7420/45034658/gkac545.pdfTest -
7دورية أكاديمية
المؤلفون: Bresser, Kaspar, Logtenberg, Meike E. W., Toebes, Mireille, Proost, Natalie, Sprengers, Justin, Siteur, Bjorn, Boeije, Manon, Kroese, Lona J., Schumacher, Ton N.
المساهمون: European Research Council
المصدر: OncoImmunology ; volume 11, issue 1 ; ISSN 2162-402X
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8دورية أكاديمية
المؤلفون: Annunziato, Stefano, Lutz, Catrin, Henneman, Linda, Bhin, Jinhyuk, Wong, Kim, Siteur, Bjørn, van Gerwen, Bas, de Korte‐Grimmerink, Renske, Zafra, Maria Paz, Schatoff, Emma M, Drenth, Anne Paulien, van der Burg, Eline, Eijkman, Timo, Mukherjee, Siddhartha, Boroviak, Katharina, Wessels, Lodewyk FA, van de Ven, Marieke, Huijbers, Ivo J, Adams, David J, Dow, Lukas E, Jonkers, Jos
المساهمون: Nederlandse Organisatie voor Wetenschappelijk Onderzoek, FP7 Ideas: European Research Council
المصدر: The EMBO Journal ; volume 39, issue 5 ; ISSN 0261-4189 1460-2075
مصطلحات موضوعية: General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, Molecular Biology, General Neuroscience
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9دورية أكاديمية
المؤلفون: Annunziato, Stefano, de Ruiter, Julian R., Henneman, Linda, Brambillasca, Chiara S., Lutz, Catrin, Vaillant, François, Ferrante, Federica, Drenth, Anne Paulien, van der Burg, Eline, Siteur, Bjørn, van Gerwen, Bas, de Bruijn, Roebi, van Miltenburg, Martine H., Huijbers, Ivo J., van de Ven, Marieke, Visvader, Jane E., Lindeman, Geoffrey J., Wessels, Lodewyk F. A., Jonkers, Jos
المصدر: Nature Communications ; volume 10, issue 1 ; ISSN 2041-1723
مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary
الوصف: BRCA1 -mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc , Met , Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling and comparative oncogenomics analysis show that MYC-overexpression strongly reshapes the CNA landscape of BRCA1-deficient mammary tumors and identify MCL1 as a collaborating driver in these tumors. Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1 -mutated cancer patients with poor response to PARPi monotherapy.
الإتاحة: https://doi.org/10.1038/s41467-019-08301-2Test
https://www.nature.com/articles/s41467-019-08301-2.pdfTest
https://www.nature.com/articles/s41467-019-08301-2Test -
10دورية أكاديمية
المؤلفون: Serresi, Michela, Siteur, Bjorn, Hulsman, Danielle, Company, Carlos, Schmitt, Matthias J., Lieftink, Cor, Morris, Ben, Cesaroni, Matteo, Proost, Natalie, Beijersbergen, Roderick L., van Lohuizen, Maarten, Gargiulo, Gaetano
المساهمون: European Union Marie Curie, Netherlands Organization for Scientific Research to Cancer Genomics Netherlands, Dutch Cancer Society, Fondazione Lorini, Max Delbrück Center, Helmholtz Association
المصدر: Journal of Experimental Medicine ; volume 215, issue 12, page 3115-3135 ; ISSN 0022-1007 1540-9538
الوصف: Kras-driven non–small-cell lung cancers (NSCLCs) are a leading cause of death with limited therapeutic options. Many NSCLCs exhibit high levels of Ezh2, the enzymatic subunit of polycomb repressive complex 2 (PRC2). We tested Ezh2 inhibitors as single agents or before chemotherapy in mice with orthotopic Kras-driven NSCLC grafts, which homogeneously express Ezh2. These tumors display sensitivity to EZH2 inhibition by GSK126 but also amplify an inflammatory program involving signaling through NF-κB and genes residing in PRC2-regulated chromatin. During this process, tumor cells overcome GSK126 antiproliferative effects. We identified oncogenes that may mediate progression through an in vivo RNAi screen aimed at targets of PRC2/NF-κB. An in vitro compound screening linked GSK126-driven inflammation and therapeutic vulnerability in human cells to regulation of RNA synthesis and proteostasis. Interestingly, GSK126-treated NSCLCs in vivo also showed an enhanced response to a combination of nimesulide and bortezomib. Thus, Ezh2 inhibition may restrict cell proliferation and promote defined adaptive responses. Targeting these responses potentially improves outcomes in Kras-driven NSCLCs.
الإتاحة: https://doi.org/10.1084/jem.20180801Test
https://rupress.org/jem/article-pdf/215/12/3115/1758385/jem_20180801.pdfTest
