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

Michaelis, Martin, Rothweiler, Florian, Nerreter, Thomas, van Rikxoort, Marijke, Zehner, Richard, Dirks, Wilhelm G, Wiese, Michael, Cinatl, Jindrich (2014) Association between acquired resistance to PLX4032 (vemurafenib) and ATP-binding cassette transporter expression. BMC research notes, 7 . p. 710. ISSN 1756-0500. (doi:10.1186/1756-0500-7-710) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1186/1756-0500-7-710

Abstract

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.

Item Type: Article
DOI/Identification number: 10.1186/1756-0500-7-710
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 13 Oct 2014 09:59 UTC
Last Modified: 29 May 2019 13:10 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/43283 (The current URI for this page, for reference purposes)
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