High-throughput screening identifies idasanutlin as a resensitizing drug for venetoclax-resistant neuroblastoma cells

Lindy Vernooij, Laurel T. Bate-Eya, Lindy K. Alles, Jasmine Y. Lee, Bianca Koopmans, Hunter C. Jonus, Nil A. Schubert, Linda Schild, Daphne Lelieveld, David A. Egan, Mark Kerstjens, Ronald W. Stam, Jan Koster, Kelly C. Goldsmith, Jan J. Molenaar, M. M.Emmy Dolman

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

3 Citaten (Scopus)

Samenvatting

Neuroblastoma tumors frequently overexpress the anti-apoptotic protein B-cell lymphoma/leukemia 2 (BCL-2). We previously showed that treating BCL-2-dependent neuroblastoma cells with the BCL-2 inhibitor venetoclax results in apoptosis, but unfortunately partial therapy resistance is observed. The current study describes the identification of drugs capable of resensitizing venetoclax-resistant neuroblastoma cells to venetoclax. To examine these effects, venetoclax resistance was induced in BCL-2-dependent neuroblastoma cell lines KCNR and SJNB12 by continuous exposure to high venetoclax concentrations. Nonresistant and venetoclax-resistant neuroblastoma cell lines were exposed to a 209-compound library in the absence and presence of venetoclax to identify compounds that were more effective in the venetoclax-resistant cell lines under venetoclax pressure. Top hits were further validated in combination with venetoclax using BCL-2-dependent neuroblastoma model systems. Overall, high-throughput drug screening identified the MDM2 inhibitor idasanutlin as a promising resensitizing agent for venetoclax-resistant neuroblastoma cell lines. Idasanutlin treatment induced BAX-mediated apoptosis in venetoclax-resistant neuroblastoma cells in the presence of venetoclax, whereas it caused p21-mediated growth arrest in control cells. In vivo combination treatment showed tumor regression and superior efficacy over single-agent therapies in a BCL-2-dependent neuroblastoma cell line xenograft and a patient-derived xenograft. However, xenografts less dependent on BCL-2 were not sensitive to venetoclax-idasanutlin combination therapy. This study demonstrates that idasanutlin can overcome resistance to the BCL-2 inhibitor venetoclax in preclinical neuroblastoma model systems, which supports clinical development of a treatment strategy combining the two therapies.

Originele taal-2Engels
Pagina's (van-tot)1161-1172
Aantal pagina's12
TijdschriftMolecular Cancer Therapeutics
Volume20
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - jun. 2021

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