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ABCB1 as predominant resistance mechanism in cells with acquired SNS-032 resistance

Löschmann, Nadine, Michaelis, Martin, Rothweiler, Florian, Voges, Yvonne, Balónová, Barbora, Blight, Barry A., Cinatl, Jindrich (2016) ABCB1 as predominant resistance mechanism in cells with acquired SNS-032 resistance. Oncotarget, 7 (36). pp. 58051-58064. ISSN 1949-2553. (doi:10.18632/oncotarget.11160)

Abstract

The CDK inhibitor SNS-032 had previously exerted promising anti-neuroblastoma activity via CDK7 and 9 inhibition. ABCB1 expression was identified as major determinant of SNS-032 resistance. Here, we investigated the role of ABCB1 in acquired SNS-032 resistance. In contrast to ABCB1-expressing UKF-NB-3 sub-lines resistant to other ABCB1 substrates, SNS-032-adapted UKF-NB-3 (UKF-NB-3rSNS- 032300nM) cells remained sensitive to the non-ABCB1 substrate cisplatin and were completely re-sensitized to cytotoxic ABCB1 substrates by ABCB1 inhibition. Moreover, UKF-NB-3rSNS-032300nM cells remained similarly sensitive to CDK7 and 9 inhibition as UKF-NB-3 cells. In contrast, SHEPrSNS-0322000nM, the SNS-032-resistant sub-line of the neuroblastoma cell line SHEP, displayed low level SNS-032 resistance also when ABCB1 was inhibited. This discrepancy may be explained by the higher SNS-032 concentrations that were used to establish SHEPrSNS-0322000nM cells, since SHEP cells intrinsically express ABCB1 and are less sensitive to SNS-032 (IC50 912 nM) than UKF-NB-3 cells (IC50 153 nM). In conclusion, we show that ABCB1 expression represents the primary (sometimes exclusive) resistance mechanism in neuroblastoma cells with acquired resistance to SNS-032. Thus, ABCB1 inhibitors may increase the SNS-032 efficacy in ABCB1-expressing cells and prolong or avoid resistance formation.

Item Type: Article
DOI/Identification number: 10.18632/oncotarget.11160
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Faculties > Sciences > School of Physical Sciences
Depositing User: Martin Michaelis
Date Deposited: 09 May 2018 10:51 UTC
Last Modified: 29 May 2019 20:31 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/66960 (The current URI for this page, for reference purposes)
Michaelis, Martin: https://orcid.org/0000-0002-5710-5888
Blight, Barry A.: https://orcid.org/0000-0003-1166-6206
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