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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Kinase inhibitors are often substrates of ATP-binding cassette (ABC) transporters.
• Increased ABC transporter expression is linked to resistance against kinase inhibitors.
• This study focuses on ABCB1, ABCC1, and ABCG2 in melanoma resistance to BRAF inhibitors PLX4032 and PLX4720.

Purpose of the Study:

• To investigate the role of ABCB1, ABCC1, and ABCG2 in acquired resistance to BRAF inhibitors (PLX4032, PLX4720) in melanoma.
• To compare the impact of BRAF inhibitors and cytotoxic ABC transporter substrates on ABC transporter expression.

Main Methods:

• Analysis of 16 V600E BRAF-mutated melanoma cell lines, including parental and resistant sub-lines.
• Assessment of acquired resistance to PLX4032, PLX4720, vincristine, and mitoxantrone.
• Measurement of ABC transporter expression levels in resistant cell lines.

Main Results:

• PLX4032 and PLX4720 similarly affected ABCC1- and ABCG2-mediated drug transport.
• Enhanced ABC transporter expression was observed in 4/4 cytotoxic substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines.
• PLX4032 demonstrated a lower potential to induce ABC transporter expression compared to PLX4720 or cytotoxic substrates.

Conclusions:

• BRAF inhibitors, particularly PLX4720 and cytotoxic substrates, can induce ABC transporter expression in melanoma.
• ABC transporters contribute to multi-drug resistance, a critical factor for designing subsequent therapies.
• Understanding ABC transporter roles is vital for overcoming resistance to BRAF inhibitor treatments in melanoma.