Association between acquired resistance to PLX4032 (vemurafenib) and ATP-binding cassette transporter expression

BMC Research Notes

Jindrich Cinatl⁶  Michael Wiese¹  Wilhelm G Dirks³  Richard Zehner⁴  Marijke van Rikxoort⁵  Thomas Nerreter⁶  Florian Rothweiler⁶  Martin Michaelis² 

[1] Pharmaceutical Institute, University of Bonn, An der Immenburg 4, Bonn 53121, Germany;Current address: Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury Kent CT2 7NJ, UK;Leibniz-Institute Deutsche Sammlung für Mikroorganismen und Zellkulturen GmbH, Inhoffenstraße 7B, Braunschweig 38124, Germany;Institut für Rechtsmedizin, Klinikum der Goethe-Universität, Kennedyallee 104, Frankfurt am Main 60596, Germany;Current address: Institute of Pharmacology and Toxicology, Biomedical Center (BMZ), University of Bonn, Bonn 53127, Germany;Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, Frankfurt am Main 60596, Germany

关键词: ABCG2;    ABCC1;    ABCB1;    Vincristine;    Mitoxantrone;    Melanoma;    Acquired drug resistance;    PLX4720;    PLX4032;    Vemurafenib;   

Others  :  1127296
DOI  :  10.1186/1756-0500-7-710

 received in 2014-08-21, accepted in 2014-10-02,  发布年份 2014

【 摘 要 】

Background

Various kinase inhibitors are known to be ATP-binding cassette (ABC) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression. Here, we investigated the role of the ABC transporters ABCB1, ABCC1, and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 (vemurafenib) and PLX4720. PLX4032 had previously been shown to interfere with ABCB1 and ABCG2. PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032.

Findings

PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion. In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub-lines with acquired resistance to PLX4032, PLX4720, vincristine (cytotoxic ABCB1 and ABCC1 substrate), or mitoxantrone (cytotoxic ABCG2 substrate), we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines.

Conclusion

PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates. Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.

【 授权许可】

   
2014 Michaelis et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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