دورية أكاديمية
Enhancing Standard of Care Chemotherapy Efficacy Using DNA-Dependent Protein Kinase (DNA-PK) Inhibition in Preclinical Models of Ewing Sarcoma.
| العنوان: | Enhancing Standard of Care Chemotherapy Efficacy Using DNA-Dependent Protein Kinase (DNA-PK) Inhibition in Preclinical Models of Ewing Sarcoma. |
|---|---|
| المؤلفون: | Collins VJ; Translational Sarcoma Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Ludwig KR; Functional Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Nelson AE; Translational Sarcoma Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Sundara Rajan S; Functional Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Yeung C; Translational Sarcoma Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Vulikh K; Molecular Histopathology Lab, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Isanogle KA; Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland., Mendoza A; Translational Sarcoma Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Difilippantonio S; Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland., Karim BO; Molecular Histopathology Lab, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Caplen NJ; Functional Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Heske CM; Translational Sarcoma Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2024 Aug 01; Vol. 23 (8), pp. 1109-1123. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | DNA-Activated Protein Kinase*/antagonists & inhibitors , DNA-Activated Protein Kinase*/metabolism , Sarcoma, Ewing*/drug therapy , Sarcoma, Ewing*/pathology, Animals ; Humans ; Mice ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Standard of Care ; Xenograft Model Antitumor Assays |
| مستخلص: | Disruption of DNA damage repair via impaired homologous recombination is characteristic of Ewing sarcoma (EWS) cells. We hypothesize that this disruption results in increased reliance on nonhomologous end joining to repair DNA damage. In this study, we investigated if pharmacologic inhibition of the enzyme responsible for nonhomologous end joining, the DNA-PK holoenzyme, alters the response of EWS cells to genotoxic standard of care chemotherapy. We used analyses of cell viability and proliferation to investigate the effects of clinical DNA-PK inhibitors (DNA-PKi) in combination with six therapeutic or experimental agents for EWS. We performed calculations of synergy using the Loewe additivity model. Immunoblotting evaluated treatment effects on DNA-PK, DNA damage, and apoptosis. Flow cytometric analyses evaluated effects on cell cycle and fate. We used orthotopic xenograft models to interrogate tolerability, drug mechanism, and efficacy in vivo. DNA-PKi demonstrated on-target activity, reducing phosphorylated DNA-PK levels in EWS cells. DNA-PKi sensitized EWS cell lines to agents that function as topoisomerase 2 (TOP2) poisons and enhanced the DNA damage induced by TOP2 poisons. Nanomolar concentrations of single-agent TOP2 poisons induced G2M arrest and little apoptotic response while adding DNA-PKi-mediated apoptosis. In vivo, the combination of AZD7648 and etoposide had limited tolerability but resulted in enhanced DNA damage, apoptosis, and EWS tumor shrinkage. The combination of DNA-PKi with standard of care TOP2 poisons in EWS models is synergistic, enhances DNA damage and cell death, and may form the basis of a promising future therapeutic strategy for EWS. (©2024 American Association for Cancer Research.) |
| References: | DNA Repair (Amst). 2008 Oct 1;7(10):1765-71. (PMID: 18675941) Sci Rep. 2023 Aug 1;13(1):12429. (PMID: 37528151) Biomed Pharmacother. 2017 Oct;94:1077-1093. (PMID: 28821159) Biomedicines. 2022 May 30;10(6):. (PMID: 35740300) Sci Rep. 2019 Dec 11;9(1):18882. (PMID: 31827119) Mol Cancer Res. 2019 Dec;17(12):2457-2468. (PMID: 31551253) Pediatr Blood Cancer. 2019 Sep;66(9):e27824. (PMID: 31157509) Cancer Res. 2016 Nov 15;76(22):6657-6668. (PMID: 27697767) Oncotarget. 2017 Jun 28;8(50):87016-87032. (PMID: 29152060) Cancer Discov. 2014 May;4(5):592-605. (PMID: 24556366) Mol Cancer Ther. 2020 May;19(5):1091-1101. (PMID: 32220971) Sci Rep. 2019 Apr 23;9(1):6359. (PMID: 31015540) Mol Cancer Ther. 2021 Nov;20(11):2151-2165. (PMID: 34413129) Clin Cancer Res. 2021 Aug 1;27(15):4353-4366. (PMID: 34011558) Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26356-26365. (PMID: 33020270) Clin Cancer Res. 2015 Feb 15;21(4):819-32. (PMID: 25500058) Front Oncol. 2020 Feb 13;10:127. (PMID: 32117773) Clin Cancer Res. 2017 Dec 1;23(23):7301-7311. (PMID: 28899971) Clin Cancer Res. 2023 Dec 15;29(24):5128-5139. (PMID: 37773632) Oncotarget. 2017 Apr 11;8(15):24679-24693. (PMID: 28160567) Cancer Res. 2012 Apr 1;72(7):1608-13. (PMID: 22287547) Cell Rep. 2014 Nov 6;9(3):829-41. (PMID: 25437539) Br J Cancer. 2015 Jun 9;112(12):1857-65. (PMID: 25989269) Sci Rep. 2022 Jan 19;12(1):974. (PMID: 35046420) Mol Cancer Ther. 2022 Apr 1;21(4):555-567. (PMID: 35149547) Nature. 2018 Mar 15;555(7696):387-391. (PMID: 29513652) Acta Pharm Sin B. 2021 Dec;11(12):3935-3949. (PMID: 35024317) Bioinformatics. 2017 Aug 01;33(15):2413-2415. (PMID: 28379339) Cell Death Discov. 2022 Feb 26;8(1):85. (PMID: 35220396) N Engl J Med. 1994 Aug 4;331(5):294-9. (PMID: 8022439) J Cancer Res Clin Oncol. 2023 Sep;149(11):8605-8617. (PMID: 37097390) ChemMedChem. 2017 Jun 21;12(12):895-900. (PMID: 28423228) Int J Mol Sci. 2019 Jul 29;20(15):. (PMID: 31362335) Radiother Oncol. 2022 Jan;166:162-170. (PMID: 34861268) Mol Cell Oncol. 2018 May 29;5(4):e1465014. (PMID: 30250915) Eur J Cancer. 2023 Sep;190:112950. (PMID: 37441939) Clin Cancer Res. 2023 Nov 1;29(21):4479-4491. (PMID: 37616468) Neoplasia. 2022 Mar;25:53-61. (PMID: 35168148) Clin Cancer Res. 2014 Mar 1;20(5):1190-203. (PMID: 24277455) Paediatr Drugs. 2023 Jul;25(4):389-397. (PMID: 37014523) Front Oncol. 2018 Jul 13;8:245. (PMID: 30057890) Curr Med Chem. 2017;24(15):1504-1519. (PMID: 27919216) Prostate. 2021 Oct;81(14):1032-1048. (PMID: 34297853) Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):15030-5. (PMID: 22927417) Sci Signal. 2017 Oct 03;10(499):. (PMID: 28974650) Clin Cancer Res. 2015 Sep 15;21(18):4184-93. (PMID: 25779942) Cancers (Basel). 2023 Dec 30;16(1):. (PMID: 38201616) Curr Opin Oncol. 2014 Jul;26(4):428-33. (PMID: 24840521) Br J Cancer. 2021 Feb;124(4):728-735. (PMID: 33230210) Nat Rev Dis Primers. 2018 Jul 5;4(1):5. (PMID: 29977059) J Pediatr Hematol Oncol. 2008 Jun;30(6):425-30. (PMID: 18525458) Genes Chromosomes Cancer. 2010 Jan;49(1):40-51. (PMID: 19787792) Cell Mol Life Sci. 2020 Jan;77(1):81-91. (PMID: 31728578) Sci Transl Med. 2013 Jun 12;5(189):189ra78. (PMID: 23761041) PLoS Genet. 2014 Jul 10;10(7):e1004475. (PMID: 25010205) Front Genet. 2020 Sep 10;11:1036. (PMID: 33133138) Cancer Res Commun. 2022 Jun;2(6):471-482. (PMID: 36338546) Mutat Res. 2020 May - Dec;821:111692. (PMID: 32172133) Genet Med. 2017 Aug;19(8):955-958. (PMID: 28125078) Pharmacol Res Perspect. 2015 Jun;3(3):e00149. (PMID: 26171228) Cancer Res. 2022 Oct 17;82(20):3815-3829. (PMID: 35972384) Am J Clin Oncol. 2017 Aug;40(4):423-428. (PMID: 25599318) Nature. 2012 Mar 28;483(7391):570-5. (PMID: 22460902) Sci Rep. 2021 Jun 9;11(1):12148. (PMID: 34108527) Oncotarget. 2016 Sep 13;7(37):58759-58767. (PMID: 27577084) Mol Cancer Res. 2020 Jan;18(1):91-104. (PMID: 31649026) Oncotarget. 2012 Feb;3(2):172-82. (PMID: 22383402) Cancer Chemother Pharmacol. 2017 Sep;80(3):645-652. (PMID: 28735378) Cell Chem Biol. 2022 Feb 17;29(2):202-214.e7. (PMID: 34329582) Nat Commun. 2019 Nov 7;10(1):5065. (PMID: 31699977) J Med Chem. 2014 Dec 26;57(24):10290-303. (PMID: 25432018) Cancer Discov. 2014 Nov;4(11):1326-41. (PMID: 25186949) Clin Cancer Res. 2016 Aug 15;22(16):4105-18. (PMID: 26979396) Cancer Discov. 2014 Nov;4(11):1342-53. (PMID: 25223734) PLoS One. 2015 Dec 30;10(12):e0145744. (PMID: 26716839) Oncotarget. 2017 Sep 28;8(69):113418-113430. (PMID: 29371919) J Biol Chem. 2018 Jul 6;293(27):10512-10523. (PMID: 29247009) |
| معلومات مُعتمدة: | ZIA BC011704 United States ImNIH Intramural NIH HHS; Z99 CA999999 United States ImNIH Intramural NIH HHS; Children's Cancer Foundation (CCF); ZIA BC 011774 National Cancer Institute (NCI); ZIA BC011774 United States ImNIH Intramural NIH HHS; Center for Cancer Research (CCR) |
| المشرفين على المادة: | EC 2.7.11.1 (DNA-Activated Protein Kinase) 0 (Protein Kinase Inhibitors) |
| تواريخ الأحداث: | Date Created: 20240424 Date Completed: 20240801 Latest Revision: 20240815 |
| رمز التحديث: | 20240815 |
| مُعرف محوري في PubMed: | PMC11293986 |
| DOI: | 10.1158/1535-7163.MCT-23-0641 |
| PMID: | 38657228 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
|---|---|
| DOI: | 10.1158/1535-7163.MCT-23-0641 |