Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma
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ORIGINAL ARTICLE
Expression and pharmacological inhibition of TrkB and EGFR in glioblastoma Kelly V. Pinheiro1,2 · Amanda Thomaz1,2,5 · Bárbara Kunzler Souza1,2,3 · Victoria Anne Metcalfe4 · Natália Hogetop Freire1 · André Tesainer Brunetto1,3 · Caroline Brunetto de Farias1,3 · Mariane Jaeger1,3 · Victorio Bambini4 · Christopher G. S. Smith4 · Lisa Shaw4 · Rafael Roesler1,2 Received: 2 March 2020 / Accepted: 25 August 2020 © Springer Nature B.V. 2020
Abstract A member of the Trk family of neurotrophin receptors, tropomyosin receptor kinase B (TrkB, encoded by the NTRK2 gene) is an increasingly important target in various cancer types, including glioblastoma (GBM). EGFR is among the most frequently altered oncogenes in GBM, and EGFR inhibition has been tested as an experimental therapy. Functional interactions between EGFR and TrkB have been demonstrated. In the present study, we investigated the role of TrkB and EGFR, and their interactions, in GBM. Analyses of NTRK2 and EGFR gene expression from The Cancer Genome Atlas (TCGA) datasets showed an increase in NTRK2 expression in the proneural subtype of GBM, and a strong correlation between NTRK2 and EGFR expression in glioma CpG island methylator phenotype (G-CIMP+) samples. We showed that when TrkB and EGFR inhibitors were combined, the inhibitory effect on A172 human GBM cells was more pronounced than when either inhibitor was given alone. When U87MG GBM cells were xenografted into the flank of nude mice, tumor growth was delayed by treatment with TrkB and EGFR inhibitors, given alone or combined, only at specific time points. Intracranial GBM growth in mice was not significantly affected by drug treatments. Our findings indicate that correlations between NTRK2 and EGFR expression occur in specific GBM subgroups. Also, our results using cultured cells suggest for the first time the potential of combining TrkB and EGFR inhibition for the treatment of GBM. Keywords Brain tumor · Epidermal growth factor receptor · Glioblastoma · Growth factor receptor · Neurotrophin · Tropomyosin receptor kinase B
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11033-020-05739-2) contains supplementary material, which is available to authorized users. * Rafael Roesler [email protected] 1
2
Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE‑HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS 90035‑003, Brazil Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), Porto Alegre, RS 90050‑170, Brazil
Growth factor receptors constitute many current and potential targets for molecularly specific therapies in cancer. The epidermal growth factor receptor (EGFR), a member of the ERBB family of transmembrane receptor tyrosine kinase (RTK) family, frequently shows gene amplification and 3
Children’s Cancer Institute, Porto Alegre, RS 90620‑110, Brazil
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