EGFRvIII Confers Sensitivity to Saracatinib in a STAT5-Dependent Manner in Glioblastoma.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

STAT5 Transcription Factor*/metabolism ; Glioblastoma*/drug therapy ; Glioblastoma*/metabolism ; Glioblastoma*/pathology ; Glioblastoma*/genetics ; Quinazolines*/pharmacology ; Quinazolines*/therapeutic use ; Benzodioxoles*/pharmacology ; Benzodioxoles*/therapeutic use ; ErbB Receptors*/metabolism ; Temozolomide*/pharmacology ; Cell Proliferation*/drug effects; Humans ; Animals ; Mice ; Phosphorylation/drug effects ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Signal Transduction/drug effects ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Brain Neoplasms/genetics ; Apoptosis/drug effects ; src-Family Kinases/metabolism ; Tumor Suppressor Proteins

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.

Neuro Oncol. 2020 Jun 9;22(6):806-818. (PMID: 31950181)
Clin Cancer Res. 2012 Aug 1;18(15):4070-9. (PMID: 22675172)
Mol Oncol. 2015 Nov;9(9):1783-98. (PMID: 26105207)
Nat Commun. 2019 Jan 16;10(1):259. (PMID: 30651547)
Cancer Cell. 2013 Oct 14;24(4):438-49. (PMID: 24135280)
Neurooncol Adv. 2020 Jun 19;2(1):vdaa078. (PMID: 32743548)
Ann Neurol. 2015 Jun;77(6):953-71. (PMID: 25707991)
J Biol Chem. 1999 Jun 11;274(24):17209-18. (PMID: 10358079)
Science. 2007 May 18;316(5827):1039-43. (PMID: 17463250)
Oncogenesis. 2016 Oct 24;5(10):e266. (PMID: 27775700)
Cold Spring Harb Perspect Biol. 2012 Mar 01;4(3):. (PMID: 22383755)
Clin Cancer Res. 2020 Mar 1;26(5):1094-1104. (PMID: 31852831)
Oncol Lett. 2018 Oct;16(4):4095-4104. (PMID: 30250528)
CNS Oncol. 2022 Jun 1;11(2):CNS87. (PMID: 35575067)
Cancers (Basel). 2020 Dec 26;13(1):. (PMID: 33375286)
Lancet. 2018 Aug 4;392(10145):432-446. (PMID: 30060998)
Cancer Res. 2005 Jul 1;65(13):5535-43. (PMID: 15994925)
J Biol Chem. 2000 Aug 11;275(32):24407-13. (PMID: 10823841)
Int J Oncol. 2011 Dec;39(6):1567-75. (PMID: 21850371)
Am J Cancer Res. 2022 Mar 15;12(3):1129-1142. (PMID: 35411230)
Mol Cancer Ther. 2013 Nov;12(11):2541-58. (PMID: 24026012)
Nat Neurosci. 2017 Aug;20(8):1074-1084. (PMID: 28604685)
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8831-5. (PMID: 7568026)
Cells. 2019 Nov 06;8(11):. (PMID: 31698775)
Nat Commun. 2019 Aug 9;10(1):3601. (PMID: 31399589)
Clin Cancer Res. 2018 Apr 15;24(8):1932-1943. (PMID: 29440177)
Oncogene. 2015 Jan 2;34(1):129-134. (PMID: 24362532)
Cell. 2017 Feb 9;168(4):629-643. (PMID: 28187285)
Int J Oncol. 2014 Jul;45(1):302-10. (PMID: 24819299)
Genes Chromosomes Cancer. 2004 Jan;39(1):29-36. (PMID: 14603439)
Neuro Oncol. 2015 Jul;17(7):992-8. (PMID: 25758746)
Front Oncol. 2019 Feb 21;9:48. (PMID: 30847297)
Clin Cancer Res. 2010 Oct 1;16(19):4876-83. (PMID: 20805299)
Oncogene. 2018 Mar;37(12):1561-1575. (PMID: 29321659)
Neuro Oncol. 2018 Jan 22;20(2):184-191. (PMID: 29016900)
J Immunol. 2015 Jan 1;194(1):21-7. (PMID: 25527793)
J Proteome Res. 2016 Dec 2;15(12):4476-4489. (PMID: 27934295)
Cell Death Dis. 2021 Sep 3;12(9):827. (PMID: 34480020)
Cell Death Dis. 2020 Feb 24;11(2):149. (PMID: 32094348)
Mol Cancer Res. 2018 Jul;16(7):1185-1195. (PMID: 29724813)
Mol Cancer Ther. 2009 Jun;8(6):1505-14. (PMID: 19509258)
Blood. 2011 Mar 24;117(12):3421-9. (PMID: 21233313)
Int J Cancer. 2013 Feb 1;132(3):509-20. (PMID: 22729867)

R01 CA271431 United States NH NIH HHS; R56 NS120348 United States NH NIH HHS

Keywords: cell signaling; glioblastoma; precision oncology; receptor tyrosine kinase

0 (STAT5 Transcription Factor)
0 (Quinazolines)
0 (epidermal growth factor receptor VIII)
0 (Benzodioxoles)
EC 2.7.10.1 (ErbB Receptors)
9KD24QGH76 (saracatinib)
0 (STAT5A protein, human)
YF1K15M17Y (Temozolomide)
0 (STAT5B protein, human)
EC 2.7.10.2 (src-Family Kinases)
0 (Tumor Suppressor Proteins)

Date Created: 20240619 Date Completed: 20240619 Latest Revision: 20240718

20240718

PMC11172708

10.3390/ijms25116279

38892466