| Title: |
P-glycoprotein as a chemotherapy resistance mechanism and biomarker of poor response in high-risk neuroblastoma |
| Authors: |
Atkinson, C; Kamili, A; Tactacan, CM; Jayatilleke, N; Rosser, SPA; Saletta, F; Gana, CC; Graber, P; Wanninayaka, A; Ignacio, RMC; Kavallaris, M; Gifford, AJ; Lock, RB; Norris, MD; Haber, M; Mayoh, C; Nath, CE; Trahair, TN; Fletcher, JI |
| Source: |
urn:ISSN:2772-610X ; Ejc Paediatric Oncology, 6, 100478 |
| Publisher Information: |
Elsevier |
| Publication Year: |
2025 |
| Collection: |
UNSW Sydney (The University of New South Wales): UNSWorks |
| Subject Terms: |
32 Biomedical and Clinical Sciences; 3202 Clinical Sciences; 3211 Oncology and Carcinogenesis; Neurosciences; Pediatric Cancer; Genetics; Orphan Drug; Precision Medicine; Rare Diseases; Neuroblastoma; Biotechnology; Pediatric Research Initiative; Human Genome; Cancer; Cancer Genomics; 5.1 Pharmaceuticals; anzsrc-for: 32 Biomedical and Clinical Sciences; anzsrc-for: 3202 Clinical Sciences; anzsrc-for: 3211 Oncology and Carcinogenesis |
| Description: |
Background: Half of all children with high-risk neuroblastoma progress or relapse. We identified ABCB1, encoding for the ATP binding cassette transporter P-glycoprotein (P-gp), as a candidate drug resistance mechanism based on differential expression in survivors and non-survivors and investigated whether P-gp expression limits the effectiveness of chemotherapy. Methods: P-gp/ABCB1 expression and regulation were assessed in tumours, PDX models in NSG mice, and cell lines by RNA-sequencing, immunohistochemistry, western blotting and through publicly available ChIP-Seq and RNA-Seq data. Response to standard-of-care induction therapies and targeted agents was assessed in vitro and in vivo using cell line and PDX models with genetic and pharmacological P-gp inhibition. Results: P-gp expression is common in high-risk neuroblastoma and elevated compared to other cancers. High relative expression at diagnosis is associated with poorer outcome, consistent with drug efflux. Pharmacological or genetic targeting of P-gp partially restores sensitivity of neuroblastoma cells to vincristine, doxorubicin, etoposide, and some targeted agents, but not to the ALK inhibitors crizotinib, ceritinib, alectinib and lorlatinib and sensitizes neuroblastoma xenografts to vincristine, extending survival. Conclusions: P-gp is a clinically relevant drug resistance mechanism for high-risk neuroblastoma. Tumour P-gp levels could inform treatment options for individual patients to avoid ineffective treatments and unnecessary toxicities. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
http://purl.org/au-research/grants/nhmrc/APP1157871; https://hdl.handle.net/1959.4/107841; https://doi.org/10.1016/j.ejcped.2025.100478 |
| DOI: |
10.1016/j.ejcped.2025.100478 |
| Availability: |
https://hdl.handle.net/1959.4/107841; https://unsworks.unsw.edu.au/bitstreams/67f4c2ca-b16f-4986-86ba-c9fa7d291cbc/download; https://doi.org/10.1016/j.ejcped.2025.100478 |
| Rights: |
open access ; https://purl.org/coar/access_right/c_abf2 ; CC-BY ; https://creativecommons.org/licenses/by/4.0/ ; free_to_read |
| Accession Number: |
edsbas.29CDC30 |
| Database: |
BASE |