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Open AccessFeature PaperArticle

Activation of ERBB4 in Glioblastoma Can Contribute to Increased Tumorigenicity and Influence Therapeutic Response

1
Oncogenic Signalling Group, Hudson Institute of Medical Research, 21–37 Wright Street, Clayton, VIC 3168, Australia
2
Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia
3
Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA 6008, Australia
4
Department of Anatomical Pathology, Monash Medical Centre, Clayton, VIC 3168, Australia
5
Department of Neurosurgery and Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
6
Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Parkville, VIC 3052, Australia
7
Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2018, 10(8), 243; https://doi.org/10.3390/cancers10080243
Received: 12 June 2018 / Revised: 17 July 2018 / Accepted: 18 July 2018 / Published: 25 July 2018
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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. View Full-Text
Keywords: GBM; EGFR; ERBB4; prognosis; therapy GBM; EGFR; ERBB4; prognosis; therapy
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Donoghue, J.F.; Kerr, L.T.; Alexander, N.W.; Greenall, S.A.; Longano, A.B.; Gottardo, N.G.; Wang, R.; Tabar, V.; Adams, T.E.; Mischel, P.S.; Johns, T.G. Activation of ERBB4 in Glioblastoma Can Contribute to Increased Tumorigenicity and Influence Therapeutic Response. Cancers 2018, 10, 243.

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