Journal Article

DKFZ-2022-02305

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png ERBB and P-glycoprotein inhibitors break resistance in relapsed neuroblastoma models through P-glycoprotein.

Rösch, L. (First author)DKFZ* ; Herter, S.DKFZ* ; Najafi, S.DKFZ* ; Ridinger, J.DKFZ* ; Peterziel, H.DKFZ* ; Cinatl, J. ; Jones, D. T. W.DKFZ* ; Michaelis, M. ; Witt, O.DKFZ* ; Oehme, I. (Last author)DKFZ*

2023
John Wiley & Sons, Inc. Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/1878-0261.13318

Abstract: Chemotherapy resistance is a persistent clinical problem in relapsed high-risk neuroblastomas. We tested a panel of 15 drugs for sensitization of neuroblastoma cells to the conventional chemotherapeutic vincristine, identifying tariquidar, an inhibitor of the transmembrane pump P-glycoprotein (P-gp/ABCB1), and the ERBB family inhibitor afatinib as the top resistance breakers. Both compounds were efficient in sensitizing neuroblastoma cells to vincristine in trypan blue exclusion assays and in inducing apoptotic cell death. The evaluation of ERBB signaling revealed no functional inhibition, i.e., dephosphorylation of the downstream pathways upon afatinib treatment but direct off-target interference with P-gp function. Depletion of ABCB1, but not ERRB4, sensitized cells to vincristine treatment. P-gp inhibition substantially broke vincristine resistance in vitro and in vivo (zebrafish embryo xenograft). The analysis of gene expression datasets of more than 50 different neuroblastoma cell lines (primary and relapsed) and more than 160 neuroblastoma patient samples from the pediatric precision medicine platform INFORM (Individualized Therapy For Relapsed Malignancies in Childhood) confirmed a pivotal role of P-gp specifically in neuroblastoma resistance at relapse, while the ERBB family appears to play a minor part.

Keyword(s): apoptotic cell death ; chemotherapy resistance ; off-target ; pediatric patient samples ; precision medicine ; zebrafish xenograft model

Note: #EA:B310#LA:B310# / 2023 Jan;17(1):37-58

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Contributing Institute(s):

1. KKE Pädiatrische Onkologie (B310)
2. DKTK HD zentral (HD01)
3. Pediatric Glioma (B360)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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