title: ABCB1 as predominant resistance mechanism in cells with acquired SNS-032 resistance.
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.
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, 60596 Frankfurt am Main, Germany.
authors: Nadine
authors: N
authors: Löschmann
authors: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, UK.
authors: Martin
authors: M
authors: Michaelis
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, 60596 Frankfurt am Main, Germany.
authors: Florian
authors: F
authors: Rothweiler
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, 60596 Frankfurt am Main, Germany.
authors: Yvonne
authors: Y
authors: Voges
authors: School of Physical Sciences, University of Kent, Canterbury, UK.
authors: Barbora
authors: B
authors: Balónová
authors: School of Physical Sciences, University of Kent, Canterbury, UK.
authors: Barry A
authors: BA
authors: Blight
authors: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, 60596 Frankfurt am Main, Germany.
authors: Jindrich
authors: J
authors: Cinatl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010080:Oxazoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D013844:Thiazoles; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000590771:3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; C000592924:BS-181; C495894:CDK2 protein, human; C467969:CDK9 protein, human; C421109:multidrug resistance-associated protein 1; C000722416:CDK7 protein, human
keywords: ABCB1; CDK inhibitor; cancer; multi-drug resistance; neuroblastoma