A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma

Abstract Three of the hallmarks of poor prognosis in paediatric ependymoma are drug resistance, local invasion and recurrence. We hypothesised that these hallmarks were due to the presence of a sub-population of cancer stem cells expressing the multi-drug efflux transporter ABCB1. ABCB1 gene express...

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Autores principales:	Durgagauri H. Sabnis, Lisa C. D. Storer, Jo-Fen Liu, Hannah K. Jackson, J. P. Kilday, Richard G. Grundy, Ian D. Kerr, Beth Coyle
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/502c6a04b51647b3a5dd47133c1f5c73
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spelling	oai:doaj.org-article:502c6a04b51647b3a5dd47133c1f5c732021-12-02T15:09:31ZA role for ABCB1 in prognosis, invasion and drug resistance in ependymoma10.1038/s41598-019-46700-z2045-2322https://doaj.org/article/502c6a04b51647b3a5dd47133c1f5c732019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46700-zhttps://doaj.org/toc/2045-2322Abstract Three of the hallmarks of poor prognosis in paediatric ependymoma are drug resistance, local invasion and recurrence. We hypothesised that these hallmarks were due to the presence of a sub-population of cancer stem cells expressing the multi-drug efflux transporter ABCB1. ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p ≤ 0.05–0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p ≤ 0.001) and invasion (p ≤ 0.001). We demonstrate that ABCB1 positive patients from an infant chemotherapy-led trial (CNS9204) had a shorter mean event free survival (EFS) (2.7 versus 8.6 years; p = 0.007 log-rank analysis) and overall survival (OS) (5.4 versus 12 years; p = 0.009 log-rank analysis). ABCB1 positivity also correlated with reduced event free survival in patients with incompletely resected tumours who received chemotherapy across CNS9204 and CNS9904 (a radiotherapy-led SIOP 1999-04 trial cohort; p = 0.03). ABCB1 is a predictive marker of chemotherapy response in ependymoma patients and vardenafil, currently used to treat paediatric pulmonary hypertension in children, could be repurposed to reduce chemoresistance, migration and invasion in paediatric ependymoma patients at non-toxic concentrations.Durgagauri H. SabnisLisa C. D. StorerJo-Fen LiuHannah K. JacksonJ. P. KildayRichard G. GrundyIan D. KerrBeth CoyleNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-9 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Durgagauri H. Sabnis Lisa C. D. Storer Jo-Fen Liu Hannah K. Jackson J. P. Kilday Richard G. Grundy Ian D. Kerr Beth Coyle A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma
description	Abstract Three of the hallmarks of poor prognosis in paediatric ependymoma are drug resistance, local invasion and recurrence. We hypothesised that these hallmarks were due to the presence of a sub-population of cancer stem cells expressing the multi-drug efflux transporter ABCB1. ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p ≤ 0.05–0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p ≤ 0.001) and invasion (p ≤ 0.001). We demonstrate that ABCB1 positive patients from an infant chemotherapy-led trial (CNS9204) had a shorter mean event free survival (EFS) (2.7 versus 8.6 years; p = 0.007 log-rank analysis) and overall survival (OS) (5.4 versus 12 years; p = 0.009 log-rank analysis). ABCB1 positivity also correlated with reduced event free survival in patients with incompletely resected tumours who received chemotherapy across CNS9204 and CNS9904 (a radiotherapy-led SIOP 1999-04 trial cohort; p = 0.03). ABCB1 is a predictive marker of chemotherapy response in ependymoma patients and vardenafil, currently used to treat paediatric pulmonary hypertension in children, could be repurposed to reduce chemoresistance, migration and invasion in paediatric ependymoma patients at non-toxic concentrations.
format	article
author	Durgagauri H. Sabnis Lisa C. D. Storer Jo-Fen Liu Hannah K. Jackson J. P. Kilday Richard G. Grundy Ian D. Kerr Beth Coyle
author_facet	Durgagauri H. Sabnis Lisa C. D. Storer Jo-Fen Liu Hannah K. Jackson J. P. Kilday Richard G. Grundy Ian D. Kerr Beth Coyle
author_sort	Durgagauri H. Sabnis
title	A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma
title_short	A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma
title_full	A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma
title_fullStr	A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma
title_full_unstemmed	A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma
title_sort	role for abcb1 in prognosis, invasion and drug resistance in ependymoma
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/502c6a04b51647b3a5dd47133c1f5c73
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A role for ABCB1 in prognosis, invasion and drug resistance in ependymoma

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