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

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.

• Authors: Martin Michaelis, Florian Rothweiler, Thomas Nerreter, Marijke van Rikxoort, Richard Zehner, Wilhelm G Dirks, Michael Wiese, Jindrich Cinatl Jr
• Journal: BMC research notes (BMC Res Notes) Vol. 7 Pg. 710 (Oct 10 2014) ISSN: 1756-0500 [Electronic] England
• PMID: 25300205 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• Indoles
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• PLX 4720
• Protein Kinase Inhibitors
• Sulfonamides
• Vemurafenib
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• multidrug resistance-associated protein 1

Topics

• ATP Binding Cassette Transporter, Subfamily B (drug effects, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (drug effects, metabolism)
• Antineoplastic Agents (metabolism, pharmacology)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Humans
• Indoles (metabolism, pharmacology)
• Melanoma (enzymology, genetics)
• Multidrug Resistance-Associated Proteins (drug effects, metabolism)
• Mutation
• Neoplasm Proteins (drug effects, metabolism)
• Protein Kinase Inhibitors (metabolism, pharmacology)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics, metabolism)
• Skin Neoplasms (enzymology, genetics)
• Sulfonamides (metabolism, pharmacology)
• Time Factors
• Vemurafenib