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

  • 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.
Metadaten
Author:Martin MichaelisORCiDGND, Florian RothweilerGND, Thomas Nerreter, Marijke van Rikxoort, Richard ZehnerORCiDGND, Wilhelm G. Dirks, Michael WieseORCiD, Jindrich CinatlORCiDGND
URN:urn:nbn:de:hebis:30:3-352693
DOI:https://doi.org/10.1186/1756-0500-7-710
ISSN:1756-0500
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/25300205
Parent Title (English):BMC Research Notes
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2014/11/04
Date of first Publication:2014/10/10
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/11/04
Tag:ABCB1; ABCC1; ABCG2; Acquired drug resistance; Melanoma; Mitoxantrone; PLX4032; PLX4720; Vemurafenib; Vincristine
Volume:7
Issue:Art. 710
Page Number:7
First Page:1
Last Page:7
Note:
Copyright © Michaelis et al.; licensee BioMed Central Ltd. 2014
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
HeBIS-PPN:366631632
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0