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

• Published in: Scientific reports Vol. 9; no. 1; pp. 10290 - 9
• Main Authors: Sabnis, Durgagauri H, Storer, Lisa C D, Liu, Jo-Fen, Jackson, Hannah K, Kilday, J P, Grundy, Richard G, Kerr, Ian D, Coyle, Beth
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.07.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemoresistance; Chemotherapy; Child, Preschool; Drug resistance; Drug Resistance, Neoplasm; Drug Synergism; Ependymoma - genetics; Ependymoma - metabolism; Ependymoma - pathology; Etoposide; Etoposide - pharmacology; Gene expression; Gene Expression Regulation, Neoplastic; Humans; Infant; Medical prognosis; Methotrexate; Methotrexate - pharmacology; Neoplasm Invasiveness; Neoplastic Stem Cells - metabolism; Neurospheres; Prognosis; Radiation therapy; Stem cells; Survival Analysis; Tumors; Up-Regulation; Vardenafil Dihydrochloride - pharmacology; Verapamil; Verapamil - pharmacology; Vincristine; Vincristine - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-46700-z

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.