Activation of ERBB4 in glioblastoma can contribute to increased tumorigenicity and influence therapeutic response

Jacqueline F. Donoghue, Lauren T. Kerr, Naomi W. Alexander, Sameer A. Greenall, Anthony B. Longano, Nicholas G. Gottardo, Rong Wang, Viviane Tabar, Timothy E. Adams, Paul S. Mischel, Terrance G. Johns

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Abstract

Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the juxtamembrane JM-a and cytoplasmic CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11% of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0 ± 3.2 months) than was no p-ERBB4 (22.5 ± 9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target.

Original languageEnglish
Article number243
Number of pages16
JournalCancers
Volume10
Issue number8
DOIs
Publication statusPublished - 1 Aug 2018

Keywords

  • EGFR
  • ERBB4
  • GBM
  • Prognosis
  • Therapy

Cite this

Donoghue, Jacqueline F. ; Kerr, Lauren T. ; Alexander, Naomi W. ; Greenall, Sameer A. ; Longano, Anthony B. ; Gottardo, Nicholas G. ; Wang, Rong ; Tabar, Viviane ; Adams, Timothy E. ; Mischel, Paul S. ; Johns, Terrance G. / Activation of ERBB4 in glioblastoma can contribute to increased tumorigenicity and influence therapeutic response. In: Cancers. 2018 ; Vol. 10, No. 8.
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abstract = "Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the juxtamembrane JM-a and cytoplasmic CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11{\%} of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0 ± 3.2 months) than was no p-ERBB4 (22.5 ± 9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target.",
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Activation of ERBB4 in glioblastoma can contribute to increased tumorigenicity and influence therapeutic response. / Donoghue, Jacqueline F.; Kerr, Lauren T.; Alexander, Naomi W.; Greenall, Sameer A.; Longano, Anthony B.; Gottardo, Nicholas G.; Wang, Rong; Tabar, Viviane; Adams, Timothy E.; Mischel, Paul S.; Johns, Terrance G.

In: Cancers, Vol. 10, No. 8, 243, 01.08.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Donoghue, Jacqueline F.

AU - Kerr, Lauren T.

AU - Alexander, Naomi W.

AU - Greenall, Sameer A.

AU - Longano, Anthony B.

AU - Gottardo, Nicholas G.

AU - Wang, Rong

AU - Tabar, Viviane

AU - Adams, Timothy E.

AU - Mischel, Paul S.

AU - Johns, Terrance G.

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KW - EGFR

KW - ERBB4

KW - GBM

KW - Prognosis

KW - Therapy

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U2 - 10.3390/cancers10080243

DO - 10.3390/cancers10080243

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