Oncotarget

Research Papers:

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

Nadine Löschmann, Martin Michaelis, Florian Rothweiler, Yvonne Voges, Barbora Balónová, Barry A. Blight and Jindrich Cinatl Jr _

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Oncotarget. 2016; 7:58051-58064. https://doi.org/10.18632/oncotarget.11160

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Abstract

Nadine Löschmann1,*, Martin Michaelis2,*, Florian Rothweiler1, Yvonne Voges1, Barbora Balónová3, Barry A. Blight3, Jindrich Cinatl Jr1

1Institut für Medizinische Virologie, Klinikum der Goethe-Universität, 60596 Frankfurt am Main, Germany

2Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, UK

3School of Physical Sciences, University of Kent, Canterbury, UK

*These authors equally contributed to this work

Correspondence to:

Jindrich Cinatl Jr, email: [email protected]

Keywords: ABCB1, CDK inhibitor, multi-drug resistance, neuroblastoma, cancer

Received: February 19, 2016     Accepted: July 27, 2016     Published: August 09, 2016

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.


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