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.
Mol Biol Rep. 2020 Sep;47(9):6817-6828. doi: 10.1007/s11033-020-05739-2. Epub 2020 Aug 29.
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.
神经营养因子受体 Trk 家族的一员，原肌球蛋白受体激酶 B（TrkB，由 NTRK2 基因编码）是包括胶质母细胞瘤（GBM）在内的多种癌症类型中日益重要的靶点。EGFR 是 GBM 中最常改变的癌基因之一，EGFR 抑制已被作为实验性治疗进行了测试。已经证明了 EGFR 和 TrkB 之间的功能相互作用。在本研究中，我们研究了 TrkB 和 EGFR 及其相互作用在 GBM 中的作用。对来自癌症基因组图谱（TCGA）数据集的 NTRK2 和 EGFR 基因表达的分析表明，在 GBM 的神经前亚型中 NTRK2 表达增加，并且在神经胶质瘤 CpG 岛甲基化表型（G-CIMP+）样本中 NTRK2 和 EGFR 表达之间存在很强的相关性。我们表明，当 TrkB 和 EGFR 抑制剂联合使用时，对 A172 人 GBM 细胞的抑制作用比单独使用任何一种抑制剂更为明显。当 U87MG GBM 细胞被异种移植到裸鼠的侧腹时，单独或联合使用 TrkB 和 EGFR 抑制剂可延迟肿瘤生长，但仅在特定时间点。药物治疗对颅内 GBM 生长没有显著影响。我们的研究结果表明，NTRK2 和 EGFR 表达之间的相关性发生在特定的 GBM 亚组中。此外，我们使用培养细胞的结果首次表明，联合使用 TrkB 和 EGFR 抑制治疗 GBM 的潜力。
