دورية أكاديمية
CDK9 inhibition as an effective therapy for small cell lung cancer.
| العنوان: | CDK9 inhibition as an effective therapy for small cell lung cancer. |
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| المؤلفون: | Valdez Capuccino L; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; CECAD Research Center, University of Cologne, Cologne, Germany., Kleitke T; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; CECAD Research Center, University of Cologne, Cologne, Germany., Szokol B; Vichem Chemie Research Ltd., Veszprém, Hungary., Svajda L; Department of Experimental Pharmacology, and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary., Martin F; Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.; Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain.; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08036, Barcelona, Spain., Bonechi F; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; CECAD Research Center, University of Cologne, Cologne, Germany., Krekó M; Vichem Chemie Research Ltd., Veszprém, Hungary.; Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary., Azami S; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; CECAD Research Center, University of Cologne, Cologne, Germany., Montinaro A; Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK., Wang Y; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; CECAD Research Center, University of Cologne, Cologne, Germany., Nikolov V; CECAD Research Center, University of Cologne, Cologne, Germany.; Cell death, inflammation and immunity laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany., Kaiser L; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany., Bonasera D; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; Cell death, inflammation and immunity laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.; Genome instability, inflammation and cell death laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany., Saggau J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; Cell death, inflammation and immunity laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.; Genome instability, inflammation and cell death laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany., Scholz T; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany., Schmitt A; University Hospital of Cologne, Medical Faculty, Department I for Internal Medicine, Cologne, Germany., Beleggia F; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University Hospital of Cologne, Medical Faculty, Department I for Internal Medicine, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Mildred Scheel School of Oncology Cologne, Cologne, Germany., Reinhardt HC; Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK partner site Essen), Essen, Germany., George J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine and University Hospital Cologne, University Hospital of Cologne, Cologne, Germany., Liccardi G; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; Genome instability, inflammation and cell death laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany., Walczak H; CECAD Research Center, University of Cologne, Cologne, Germany.; Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.; Cell death, inflammation and immunity laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany., Tóvári J; Department of Experimental Pharmacology, and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary., Brägelmann J; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Mildred Scheel School of Oncology Cologne, Cologne, Germany., Montero J; Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.; Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain.; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08036, Barcelona, Spain., Sos ML; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.; Division for Translational Oncology, German Cancer Research Center (DKFZ), The German Consortium for Translational Cancer Research (DKTK), München Partner Site, Ludwig-Maximilian University München, Munich, Germany., Őrfi L; Vichem Chemie Research Ltd., Veszprém, Hungary.; Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary., Peltzer N; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany. m.peltzer@uni-koeln.de.; University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany. m.peltzer@uni-koeln.de.; CECAD Research Center, University of Cologne, Cologne, Germany. m.peltzer@uni-koeln.de. |
| المصدر: | Cell death & disease [Cell Death Dis] 2024 May 20; Vol. 15 (5), pp. 345. Date of Electronic Publication: 2024 May 20. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101524092 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-4889 (Electronic) NLM ISO Abbreviation: Cell Death Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London : Nature Pub. Group |
| مواضيع طبية MeSH: | Cyclin-Dependent Kinase 9*/antagonists & inhibitors , Cyclin-Dependent Kinase 9*/metabolism , Small Cell Lung Carcinoma*/drug therapy , Small Cell Lung Carcinoma*/pathology , Lung Neoplasms*/drug therapy , Lung Neoplasms*/pathology , Pyridinium Compounds*/pharmacology , Pyridinium Compounds*/therapeutic use , Indolizines*/pharmacology, Humans ; Animals ; Cell Line, Tumor ; Mice ; Cyclic N-Oxides/pharmacology ; Apoptosis/drug effects ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use |
| مستخلص: | Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC. (© 2024. The Author(s).) |
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| معلومات مُعتمدة: | A27323 Cancer Research UK (CRUK); 70115679 Deutsche Krebshilfe (German Cancer Aid); 413326622 Deutsche Forschungsgemeinschaft (German Research Foundation); 414786233 Deutsche Forschungsgemeinschaft (German Research Foundation); 455784452 Deutsche Forschungsgemeinschaft (German Research Foundation); EKFS-2014-A06 Else Kröner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation); United Kingdom WT_ Wellcome Trust; 70113041 Deutsche Krebshilfe (German Cancer Aid); MR/S00811X/1 RCUK | Medical Research Council (MRC); 1117240 Deutsche Krebshilfe (German Cancer Aid) |
| المشرفين على المادة: | 0 (CDK9 protein, human) 0 (dinaciclib) |
| تواريخ الأحداث: | Date Created: 20240520 Date Completed: 20240520 Latest Revision: 20240528 |
| رمز التحديث: | 20240528 |
| مُعرف محوري في PubMed: | PMC11106072 |
| DOI: | 10.1038/s41419-024-06724-4 |
| PMID: | 38769311 |
| قاعدة البيانات: | MEDLINE |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 2041-4889 |
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| DOI: | 10.1038/s41419-024-06724-4 |