دورية أكاديمية
أعرض في EDS

Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma.

التفاصيل البيبلوغرافية
العنوان: Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma.
المؤلفون: Prosz A; Danish Cancer Institute, Copenhagen, Denmark., Duan H; Center for Personalized Cancer Therapy, University of Massachusetts, Boston, MA, USA.; Department of Biology, University of Massachusetts, Boston, MA, USA., Tisza V; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.; Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary., Sahgal P; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology (MIT), Harvard University, Cambridge, MA, USA., Topka S; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Niehaus Center for Inherited Cancer Genomics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Klus GT; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Börcsök J; Danish Cancer Institute, Copenhagen, Denmark.; Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark., Sztupinszki Z; Danish Cancer Institute, Copenhagen, Denmark.; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA., Hanlon T; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Diossy M; Danish Cancer Institute, Copenhagen, Denmark.; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA., Vizkeleti L; Department of Bioinformatics, Semmelweis University, Budapest, Hungary., Stormoen DR; Department of Oncology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark., Csabai I; Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary., Pappot H; Department of Oncology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark., Vijai J; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Niehaus Center for Inherited Cancer Genomics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering, New York, NY, USA., Offit K; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Niehaus Center for Inherited Cancer Genomics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering, New York, NY, USA., Ried T; Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA., Sethi N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of Massachusetts Institute of Technology (MIT), Harvard University, Cambridge, MA, USA., Mouw KW; Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark.; Department of Radiation Oncology, Brigham & Women's Hospital, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Spisak S; Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary. spisak.sandor@ttk.hu., Pathania S; Center for Personalized Cancer Therapy, University of Massachusetts, Boston, MA, USA. Shailja.Pathania@umb.edu.; Department of Biology, University of Massachusetts, Boston, MA, USA. Shailja.Pathania@umb.edu., Szallasi Z; Danish Cancer Institute, Copenhagen, Denmark. zoltan.szallasi@childrens.harvard.edu.; Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA. zoltan.szallasi@childrens.harvard.edu.; Department of Bioinformatics, Semmelweis University, Budapest, Hungary. zoltan.szallasi@childrens.harvard.edu.
المصدر: Scientific reports [Sci Rep] 2023 Nov 23; Vol. 13 (1), pp. 20567. Date of Electronic Publication: 2023 Nov 23.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Carcinoma, Renal Cell*/drug therapy , Carcinoma, Renal Cell*/genetics , Sesquiterpenes* , Kidney Neoplasms*/drug therapy , Kidney Neoplasms*/genetics, Humans ; DNA Repair ; DNA Damage ; Ultraviolet Rays ; Xeroderma Pigmentosum Group D Protein/genetics
مستخلص: Due to a demonstrated lack of DNA repair deficiencies, clear cell renal cell carcinoma (ccRCC) has not benefitted from targeted synthetic lethality-based therapies. We investigated whether nucleotide excision repair (NER) deficiency is present in an identifiable subset of ccRCC cases that would render those tumors sensitive to therapy targeting this specific DNA repair pathway aberration. We used functional assays that detect UV-induced 6-4 pyrimidine-pyrimidone photoproducts to quantify NER deficiency in ccRCC cell lines. We also measured sensitivity to irofulven, an experimental cancer therapeutic agent that specifically targets cells with inactivated transcription-coupled nucleotide excision repair (TC-NER). In order to detect NER deficiency in clinical biopsies, we assessed whole exome sequencing data for the presence of an NER deficiency associated mutational signature previously identified in ERCC2 mutant bladder cancer. Functional assays showed NER deficiency in ccRCC cells. Some cell lines showed irofulven sensitivity at a concentration that is well tolerated by patients. Prostaglandin reductase 1 (PTGR1), which activates irofulven, was also associated with this sensitivity. Next generation sequencing data of the cell lines showed NER deficiency-associated mutational signatures. A significant subset of ccRCC patients had the same signature and high PTGR1 expression. ccRCC cell line-based analysis showed that NER deficiency is likely present in this cancer type. Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells.
(© 2023. The Author(s).)
التعليقات: Update of: bioRxiv. 2023 Feb 07;:. (PMID: 36798363)
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معلومات مُعتمدة: R15 CA235436 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; P50 CA221745 United States CA NCI NIH HHS; R01 CA272657 United States CA NCI NIH HHS; R01CA272657 United States CA NCI NIH HHS
المشرفين على المادة: 6B799IH05A (irofulven)
0 (Sesquiterpenes)
EC 5.99.- (ERCC2 protein, human)
EC 3.6.4.12 (Xeroderma Pigmentosum Group D Protein)
تواريخ الأحداث: Date Created: 20231123 Date Completed: 20231127 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC10667362
DOI: 10.1038/s41598-023-47946-4
PMID: 37996508
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-023-47946-4