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ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease

Lookup NU author(s): Dr Richard Gilbertson, Roberto Hernan, Dr Adrian Frank, Professor David Ellison


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Purpose: This study was designed to investigate the biological and therapeutic significance of ERBB1, ERBB2, ERBB3, and ERBB4 in childhood ependymoma. Experimental Design: The expression frequency and clinical significance of ERBB1-4 was analyzed in a large cohort of pediatric ependymoma (n = 121) using immunohistochemistry, Western blotting, and reverse transcription-PCR analysis. Histological markers of anaplasia (necrosis, microvascular proliferation, and Ki-67 proliferative index) were also determined. Functional assessment of ERBB-dependent cell signaling and proliferation, in addition to novel therapeutic inhibition of these processes, was conducted using short-term cultures of human ependymoma cells. Results: Coexpression of ERBB2 and ERBB4 was identified in over 75% of tumors. High-level coexpression of these receptors was significantly related to tumor proliferative activity [P < 0.05; Ki-67 labeling index (LI)] and, in combined survival analysis of clinical (degree of surgical resection) and molecular (ERBB2/ERBB4 expression status and Ki-67 LI) factors, enabled a greater resolution of patient prognosis than any individual variable alone. Ligand-dependent activation of ERBB receptor-signaling in cultured ependymoma cells resulted in AKT phosphorylation and cellular proliferation that was significantly blocked in a dose-dependent manner using WAY-177820, a novel inhibitor of ERBB2 tyrosine kinase activity. Conclusions: This study suggests that ERBB receptor signaling results in aggressive disease behavior in ependymoma by promoting tumor cell proliferation. An analysis of ERBB2 and ERBB4 expression, in association with Ki-67 LI and the degree of surgical resection, may provide an accurate tool for assessing disease risk in children with this disease. In addition, these receptors may serve as a target for novel therapeutic approaches in ependymoma.

Publication metadata

Author(s): Frank AJ; Ellison DW; Hernan R; Gilbertson RJ; Bentley L; Junttila TT; Haapasalo H; Connelly M; Wetmore C; Curran T; Elenius K

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2002

Volume: 8

Issue: 10

Pages: 3054-3064

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research