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

// Nadine Loschmann 1, * , Martin Michaelis 2, * , Florian Rothweiler 1 , Yvonne Voges 1 , Barbora Balonova 3 , Barry A. Blight 3 , Jindrich Cinatl Jr 1 1 Institut fur Medizinische Virologie, Klinikum der Goethe-Universitat, 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 * These authors equally contributed to this work Correspondence to: Jindrich Cinatl Jr, email: Cinatl@em.uni-frankfurt.de 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-3 r SNS- 032 300nM ) 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-032 300nM cells remained similarly sensitive to CDK7 and 9 inhibition as UKF-NB-3 cells. In contrast, SHEPrSNS-032 2000nM , 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-032 2000nM cells, since SHEP cells intrinsically express ABCB1 and are less sensitive to SNS-032 (IC 50 912 nM) than UKF-NB-3 cells (IC 50 153 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.