دورية أكاديمية
أعرض في EDS

Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.

التفاصيل البيبلوغرافية
العنوان: Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization.
المؤلفون: Chen J; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.; Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China., Laverty DJ; Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA., Talele S; Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55905, USA., Bale A; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA., Carlson BL; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA., Porath KA; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA., Bakken KK; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA., Burgenske DM; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA., Decker PA; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA., Vaubel RA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA., Eckel-Passow JE; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA., Bhargava R; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA., Lou Z; Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA., Hamerlik P; AstraZeneca, Cambridge, UK., Harley B; Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA., Elmquist WF; Department of Pharmaceutics, University of Minnesota, Minneapolis, MN 55905, USA., Nagel ZD; Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA., Gupta SK; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA., Sarkaria JN; Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA.
المصدر: Science translational medicine [Sci Transl Med] 2024 Feb 14; Vol. 16 (734), pp. eadj5962. Date of Electronic Publication: 2024 Feb 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Association for the Advancement of Science
مواضيع طبية MeSH: Tumor Suppressor Protein p53*/genetics , Tumor Suppressor Protein p53*/metabolism , Glioblastoma*/drug therapy , Glioblastoma*/genetics , Glioblastoma*/radiotherapy , Pyridines* , Quinolones*, Humans ; Signal Transduction ; DNA Repair/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism
مستخلص: ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G 0 -G 1 arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53 -mutant tumors but not in TP53 -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53 -mutant, but not in TP53 -WT, PDXs. In plasmid-based reporter assays, GBM43 ( TP53 -mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53 (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53 -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53 -mutant cells to ATM inhibitor-mediated radiosensitization.
References: J Clin Invest. 2021 Jan 4;131(1):. (PMID: 32990677)
Mol Cell. 2017 Jun 15;66(6):801-817. (PMID: 28622525)
Curr Biol. 1998 Jan 29;8(3):145-55. (PMID: 9443911)
Int J Radiat Oncol Biol Phys. 2021 Dec 1;111(5):e54-e62. (PMID: 34400266)
Nat Protoc. 2021 Sep;16(9):4265-4298. (PMID: 34363069)
Nature. 1995 Oct 12;377(6549):552-7. (PMID: 7566157)
Cold Spring Harb Perspect Biol. 2013 Sep 01;5(9):. (PMID: 24003211)
J Pharmacol Exp Ther. 2022 Oct;383(1):91-102. (PMID: 36137710)
Cancer Res. 1998 Oct 1;58(19):4375-82. (PMID: 9766667)
Nucleic Acids Res. 2015 Mar 31;43(6):3154-66. (PMID: 25753674)
J Immunol Methods. 2009 Aug 15;347(1-2):70-8. (PMID: 19567251)
Annu Rev Pathol. 2010;5:99-118. (PMID: 20078217)
J Natl Cancer Inst Monogr. 2019 Aug 1;2019(53):. (PMID: 31425601)
Genes Dev. 2016 Nov 15;30(22):2500-2512. (PMID: 27940962)
Radiat Oncol. 2013 Apr 24;8:98. (PMID: 23617930)
J Cell Biol. 2000 Dec 25;151(7):1381-90. (PMID: 11134068)
Nat Rev Mol Cell Biol. 2021 Dec;22(12):796-814. (PMID: 34429537)
Nucleic Acids Res. 2017 Feb 17;45(3):1270-1280. (PMID: 28180309)
Genes Dev. 2009 Aug 15;23(16):1895-909. (PMID: 19608766)
Radiother Oncol. 2011 Oct;101(1):7-12. (PMID: 21737170)
Cancers (Basel). 2022 Sep 17;14(18):. (PMID: 36139666)
Cancers (Basel). 2021 Feb 18;13(4):. (PMID: 33670536)
Nat Struct Mol Biol. 2023 Apr;30(4):475-488. (PMID: 36959262)
Cancer Res. 1995 Nov 15;55(22):5187-90. (PMID: 7585571)
Nucleic Acids Res. 2012 Sep 1;40(17):8336-47. (PMID: 22730303)
Biophys Chem. 2010 Nov;152(1-3):164-9. (PMID: 20970241)
EMBO Rep. 2006 Feb;7(2):219-24. (PMID: 16322760)
Mol Cancer Ther. 2018 Aug;17(8):1637-1647. (PMID: 29769307)
Nucleic Acids Res. 2016 Jan 8;44(1):164-74. (PMID: 26384566)
Mol Cancer Ther. 2022 Jun 1;21(6):859-870. (PMID: 35405736)
Science. 1998 Sep 11;281(5383):1674-7. (PMID: 9733514)
Neurooncol Adv. 2021 Feb 04;3(1):vdab015. (PMID: 33738447)
Nature. 2000 Mar 2;404(6773):42-9. (PMID: 10716435)
Nat Rev Mol Cell Biol. 2005 Jan;6(1):44-55. (PMID: 15688066)
Nat Rev Mol Cell Biol. 2013 May;14(5):297-306. (PMID: 23594950)
Nature. 2000 Oct 5;407(6804):645-8. (PMID: 11034215)
Med Sci Monit. 2020 Oct 09;26:e925754. (PMID: 33077704)
Appl Spectrosc. 2015 Jan;69(1):154-64. (PMID: 25588232)
Signal Transduct Target Ther. 2020 May 1;5(1):60. (PMID: 32355263)
Nat Genet. 1997 Aug;16(4):397-401. (PMID: 9241281)
Nat Protoc. 2014 Aug;9(8):1771-91. (PMID: 24992094)
Genes (Basel). 2021 Aug 31;12(9):. (PMID: 34573351)
Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210. (PMID: 23847781)
Neuro Oncol. 2019 Dec 17;21(12):1519-1528. (PMID: 31832685)
Oncogene. 2005 Mar 3;24(10):1738-48. (PMID: 15674334)
CA Cancer J Clin. 2021 Sep;71(5):381-406. (PMID: 34427324)
Cell. 1996 Jul 12;86(1):159-71. (PMID: 8689683)
Mol Cell Biol. 2002 May;22(10):3247-54. (PMID: 11971958)
Sci Adv. 2018 Jun 20;4(6):eaat1719. (PMID: 29938225)
Nat Rev Cancer. 2008 Mar;8(3):193-204. (PMID: 18256616)
Curr Protoc Pharmacol. 2011 Mar;Chapter 14:Unit 14.16. (PMID: 21743824)
Clin Cancer Res. 2013 Jun 15;19(12):3189-200. (PMID: 23620409)
Cancer Inform. 2020 Apr 15;19:1176935120915839. (PMID: 32313423)
Oncogene. 2017 Jul 13;36(28):3943-3956. (PMID: 28288132)
Cell Death Dis. 2016 Dec 1;7(12):e2493. (PMID: 27906190)
J Natl Cancer Inst. 2010 Oct 20;102(20):1536-46. (PMID: 20858887)
Mol Cell. 2013 Feb 21;49(4):657-67. (PMID: 23273981)
Elife. 2021 Sep 03;10:. (PMID: 34477552)
Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2113233119. (PMID: 35235448)
J Biol Chem. 2002 Aug 30;277(35):31980-7. (PMID: 12080066)
EMBO Rep. 2009 Jun;10(6):629-35. (PMID: 19444312)
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12985-90. (PMID: 12242345)
Genes Dev. 1996 Apr 1;10(7):826-35. (PMID: 8846919)
Science. 1998 May 15;280(5366):1089-91. (PMID: 9582124)
J Natl Cancer Inst. 2015 Nov 27;108(5):. (PMID: 26615020)
Nat Rev Mol Cell Biol. 2014 Jan;15(1):7-18. (PMID: 24326623)
Cancer Drug Resist. 2021;4:244-263. (PMID: 34337349)
Cold Spring Harb Perspect Med. 2016 May 02;6(5):. (PMID: 27048304)
Neuro Oncol. 2018 Jan 22;20(2):184-191. (PMID: 29016900)
Bioinformatics. 2016 Sep 15;32(18):2866-8. (PMID: 27153664)
Nat Rev Clin Oncol. 2019 Feb;16(2):81-104. (PMID: 30356138)
Clin Cancer Res. 2014 Jul 15;20(14):3730-41. (PMID: 24838527)
J Biol Chem. 2001 Nov 9;276(45):42462-7. (PMID: 11571274)
Cell. 2007 May 18;129(4):665-79. (PMID: 17512402)
J Med Chem. 2018 May 10;61(9):3823-3841. (PMID: 29683659)
Cell. 2010 Apr 16;141(2):243-54. (PMID: 20362325)
معلومات مُعتمدة: P41 EB031772 United States EB NIBIB NIH HHS; U01 CA227954 United States CA NCI NIH HHS; R01 CA264600 United States CA NCI NIH HHS; R03 CA201612 United States CA NCI NIH HHS; T32 HL007118 United States HL NHLBI NIH HHS; U19 CA264362 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Tumor Suppressor Protein p53)
0 (AZD1390)
EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
EC 2.7.11.1 (ATM protein, human)
0 (Pyridines)
0 (Quinolones)
تواريخ الأحداث: Date Created: 20240214 Date Completed: 20240216 Latest Revision: 20240504
رمز التحديث: 20240504
مُعرف محوري في PubMed: PMC11064970
DOI: 10.1126/scitranslmed.adj5962
PMID: 38354228
قاعدة البيانات: MEDLINE
الوصف
تدمد:1946-6242
DOI:10.1126/scitranslmed.adj5962