EGFR amplification and EGFRvIII predict and participate in TAT-Cx43266-283 antitumor response in preclinical glioblastoma models.

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  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: England NLM ID: 100887420 Publication Model: Print Cited Medium: Internet ISSN: 1523-5866 (Electronic) Linking ISSN: 15228517 NLM ISO Abbreviation: Neuro Oncol Subsets: MEDLINE
    • Publication Information:
      Publication: 2010- : Oxford : Oxford University Press
      Original Publication: 1999-<2002> : Charlottesville, VA : Carden Jennings Pub.,
    • Subject Terms:
      Glioblastoma*/drug therapy ; Glioblastoma*/pathology ; Glioblastoma*/metabolism ; ErbB Receptors*/genetics ; ErbB Receptors*/metabolism ; Brain Neoplasms*/drug therapy ; Brain Neoplasms*/pathology ; Brain Neoplasms*/metabolism ; Gene Amplification* ; Temozolomide*/pharmacology ; Xenograft Model Antitumor Assays*; Animals ; Humans ; Mice ; Erlotinib Hydrochloride/pharmacology ; Tumor Cells, Cultured ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/pathology ; Neoplastic Stem Cells/metabolism
    • Abstract:
      Background: Glioblastoma (GBM) commonly displays epidermal growth factor receptor (EGFR) alterations (mainly amplification and EGFRvIII) and TAT-Cx43266-283 is a Src-inhibitory peptide with antitumor properties in preclinical GBM models. Given the link between EGFR and Src, the aim of this study was to explore the role of EGFR in the antitumor effects of TAT-Cx43266-283.
      Methods: The effect of TAT-Cx43266-283, temozolomide (TMZ), and erlotinib (EGFR inhibitor) was studied in patient-derived GBM stem cells (GSCs) and murine neural stem cells (NSCs) with and without EGFR alterations, in vitro and in vivo. EGFR alterations were analyzed by western blot and fluorescence in situ hybridization in these cells, and compared with Src activity and survival in GBM samples from The Cancer Genome Atlas.
      Results: The effect of TAT-Cx43266-283 correlated with EGFR alterations in a set of patient-derived GSCs and was stronger than that exerted by TMZ and erlotinib. In fact, TAT-Cx43266-283 only affected NSCs with EGFR alterations, but not healthy NSCs. EGFR alterations correlated with Src activity and poor survival in GBM patients. Finally, tumors generated from NSCs with EGFR alterations showed a decrease in growth, invasiveness, and vascularization after treatment with TAT-Cx43266-283, which enhanced the survival of immunocompetent mice.
      Conclusions: Clinically relevant EGFR alterations are predictors of TAT-Cx43266-283 response and part of its mechanism of action, even in TMZ- and erlotinib-resistant GSCs. TAT-Cx43266-283 targets NSCs with GBM-driver mutations, including EGFR alterations, in an immunocompetent GBM model in vivo, suggesting a promising effect on GBM recurrence. Together, this study represents an important step toward the clinical application of TAT-Cx43266-283.
      (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
    • References:
      Nature. 2012 Aug 23;488(7412):522-6. (PMID: 22854781)
      Neuro Oncol. 2020 Apr 15;22(4):493-504. (PMID: 31883012)
      Stem Cell Reports. 2017 Aug 8;9(2):451-463. (PMID: 28712848)
      J Cell Sci. 2011 Sep 1;124(Pt 17):2938-50. (PMID: 21878501)
      Br J Cancer. 2019 Apr;120(8):791-796. (PMID: 30880334)
      Nat Rev Cancer. 2015 May;15(5):302-10. (PMID: 25855404)
      Nat Rev Neurol. 2022 Sep;18(9):515-529. (PMID: 35729337)
      Int J Oncol. 2014 Jul;45(1):302-10. (PMID: 24819299)
      Mol Cancer Res. 2018 Jul;16(7):1185-1195. (PMID: 29724813)
      EBioMedicine. 2020 Dec;62:103134. (PMID: 33254027)
      Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6981-5. (PMID: 7542783)
      Cancer Biol Ther. 2011 Oct 15;12(8):718-26. (PMID: 21775822)
      Cell Death Dis. 2014 Jan 23;5:e1023. (PMID: 24457967)
      Oncotarget. 2016 Aug 2;7(31):49819-49833. (PMID: 27391443)
      Sci Transl Med. 2020 Jan 22;12(527):. (PMID: 31969485)
      Oncol Lett. 2017 Jul;14(1):512-516. (PMID: 28693199)
      J Biol Chem. 1999 Mar 19;274(12):8335-43. (PMID: 10075741)
      J Neurooncol. 2010 May;97(3):323-37. (PMID: 19855928)
      J Exp Med. 1999 Jan 4;189(1):111-21. (PMID: 9874568)
      Neuro Oncol. 2014 Oct;16 Suppl 8:viii1-6. (PMID: 25342599)
      Mol Cancer. 2012 Sep 25;11:73. (PMID: 23009336)
      Cell Res. 2021 Jun;31(6):684-702. (PMID: 33390587)
      Neuro Oncol. 2016 Dec;18(12):1644-1655. (PMID: 27286795)
      Clin Cancer Res. 2013 Jan 15;19(2):380-92. (PMID: 23213056)
      Cancers (Basel). 2023 Jan 21;15(3):. (PMID: 36765632)
      Cancer Cell. 2009 Jan 6;15(1):45-56. (PMID: 19111880)
      Nat Biotechnol. 2009 Jan;27(1):77-83. (PMID: 19098899)
      EMBO J. 2000 Feb 15;19(4):623-30. (PMID: 10675331)
      J Biol Chem. 1995 Jun 30;270(26):15591-7. (PMID: 7797556)
      Biochem Biophys Res Commun. 1995 May 25;210(3):844-51. (PMID: 7539262)
      Cancer Discov. 2012 May;2(5):401-4. (PMID: 22588877)
      Cell. 2013 Oct 10;155(2):462-77. (PMID: 24120142)
      Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1415-20. (PMID: 9990038)
      Trends Pharmacol Sci. 2012 Mar;33(3):122-8. (PMID: 22153719)
      J Neurooncol. 2012 Jul;108(3):499-506. (PMID: 22407177)
      Nat Neurosci. 2019 Apr;22(4):545-555. (PMID: 30778149)
      Oncogene. 2009 Apr 23;28(16):1821-32. (PMID: 19305428)
      Mol Oncol. 2010 Oct;4(5):420-30. (PMID: 20801091)
      Cancer Res. 2007 May 1;67(9):4164-72. (PMID: 17483327)
      Nature. 2018 Aug;560(7717):243-247. (PMID: 30069053)
      Neuro Oncol. 2021 Aug 2;23(8):1231-1251. (PMID: 34185076)
      Cancer Lett. 2015 Dec 1;369(1):86-96. (PMID: 26254539)
      Cell. 2021 Apr 29;184(9):2454-2470.e26. (PMID: 33857425)
      Sci Rep. 2021 Dec 1;11(1):23202. (PMID: 34853344)
      J Clin Oncol. 2009 Mar 10;27(8):1268-74. (PMID: 19204207)
      Cell Rep. 2022 Jun 21;39(12):110991. (PMID: 35732128)
      Oncogene. 2010 Oct 21;29(42):5712-23. (PMID: 20676131)
      Oncogene. 2022 Nov;41(45):4917-4928. (PMID: 36217026)
      Cancers (Basel). 2021 Aug 24;13(17):. (PMID: 34503072)
    • Grant Information:
      SA125P20 Junta de Castilla y León; CD21/00080 IBSAL; Instituto de Salud Carlos III; Cleveland Clinic Lerner Research Institute and Case Comprehensive Center; Ministerio de Ciencia e Innovación
    • Contributed Indexing:
      Keywords: EGFR; NSCs; Src; cell-penetrating peptides; glioblastoma
    • Accession Number:
      EC 2.7.10.1 (ErbB Receptors)
      EC 2.7.10.1 (EGFR protein, human)
      YF1K15M17Y (Temozolomide)
      0 (epidermal growth factor receptor VIII)
      DA87705X9K (Erlotinib Hydrochloride)
    • Publication Date:
      Date Created: 20240320 Date Completed: 20240706 Latest Revision: 20240801
    • Publication Date:
      20240801
    • Accession Number:
      PMC11226870
    • Accession Number:
      10.1093/neuonc/noae060
    • Accession Number:
      38507464