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Oncotarget. 2016 Sep 6;7(36):58051-58064. doi: 10.18632/oncotarget.11160.

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

Author information

1
Institut für Medizinische Virologie, Klinikum der Goethe-Universität, 60596 Frankfurt am Main, Germany.
2
Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, UK.
3
School of Physical Sciences, University of Kent, Canterbury, UK.

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.

KEYWORDS:

ABCB1; CDK inhibitor; cancer; multi-drug resistance; neuroblastoma

PMID:
27517323
PMCID:
PMC5295411
DOI:
10.18632/oncotarget.11160
[Indexed for MEDLINE]
Free PMC Article

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