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

Michaelis M, Rothweiler F, Nerreter T, van Rikxoort M, Zehner R, Dirks WG, Wiese M, Cinatl J - BMC Res Notes (2014)

Bottom Line: 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.PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion.Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.

View Article: PubMed Central - PubMed

Affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str, 40, Frankfurt am Main 60596, Germany. Cinatl@em.uni-frankfurt.de.

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.

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Expression of ABCB1, ABCC1, and ABCG2 in V600 BRAF-mutated melanoma cells adapted to PLX4032, PLX4720, or the cytotoxic ABC transporter substrates vincristine (VCR) or mitoxantrone (MITOX) relative to the respective parental cell lines. White and black bars are used to facilitate the identification of resistant sub-lines that are derived from the same parental cell line. *P < 0.05 relative to parental cells.
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Fig3: Expression of ABCB1, ABCC1, and ABCG2 in V600 BRAF-mutated melanoma cells adapted to PLX4032, PLX4720, or the cytotoxic ABC transporter substrates vincristine (VCR) or mitoxantrone (MITOX) relative to the respective parental cell lines. White and black bars are used to facilitate the identification of resistant sub-lines that are derived from the same parental cell line. *P < 0.05 relative to parental cells.

Mentions: Next, we investigated the expression of ABCB1, ABCC1, and ABCG2 in the V600E BRAF-mutated melanoma cell lines Colo-679, IGR-39, MelHO, and RVH-421 (DSMZ, Braunschweig, Germany) and their sub-lines with acquired resistance to PLX4032 (Colo-679rPLX403210 μM, MelHOrPLX403210 μM, IGR-39rPLX403220 μM, RVH-421rPLX403210 μM), PLX4720 (Colo-679rPLX472010 μM, MelHOrPLX472010 μM, IGR-39rPLX472020 μM, RVH-421rPLX472010 μM), vincristine (Colo-679rVCR20, IGR-39rVCR10, MelHOrVCR20), or mitoxantrone (RVH-421rMitox10) (Figure 3; Additional file 6: Table S5) that were derived from the Resistant Cancer Cell Line (RCCL) collection (http://www.kent.ac.uk/stms/cmp/RCCL/RCCLabout.html). Treatment of melanoma cells with PLX4032 or cytotoxic anti-cancer drugs had been shown to result in the selection of ABCB5-expressing cells [25]. However, we did not detect enhanced ABCB5 expression in our resistance models relative to the parental sensitive cells.Figure 3


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

Michaelis M, Rothweiler F, Nerreter T, van Rikxoort M, Zehner R, Dirks WG, Wiese M, Cinatl J - BMC Res Notes (2014)

Expression of ABCB1, ABCC1, and ABCG2 in V600 BRAF-mutated melanoma cells adapted to PLX4032, PLX4720, or the cytotoxic ABC transporter substrates vincristine (VCR) or mitoxantrone (MITOX) relative to the respective parental cell lines. White and black bars are used to facilitate the identification of resistant sub-lines that are derived from the same parental cell line. *P < 0.05 relative to parental cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197243&req=5

Fig3: Expression of ABCB1, ABCC1, and ABCG2 in V600 BRAF-mutated melanoma cells adapted to PLX4032, PLX4720, or the cytotoxic ABC transporter substrates vincristine (VCR) or mitoxantrone (MITOX) relative to the respective parental cell lines. White and black bars are used to facilitate the identification of resistant sub-lines that are derived from the same parental cell line. *P < 0.05 relative to parental cells.
Mentions: Next, we investigated the expression of ABCB1, ABCC1, and ABCG2 in the V600E BRAF-mutated melanoma cell lines Colo-679, IGR-39, MelHO, and RVH-421 (DSMZ, Braunschweig, Germany) and their sub-lines with acquired resistance to PLX4032 (Colo-679rPLX403210 μM, MelHOrPLX403210 μM, IGR-39rPLX403220 μM, RVH-421rPLX403210 μM), PLX4720 (Colo-679rPLX472010 μM, MelHOrPLX472010 μM, IGR-39rPLX472020 μM, RVH-421rPLX472010 μM), vincristine (Colo-679rVCR20, IGR-39rVCR10, MelHOrVCR20), or mitoxantrone (RVH-421rMitox10) (Figure 3; Additional file 6: Table S5) that were derived from the Resistant Cancer Cell Line (RCCL) collection (http://www.kent.ac.uk/stms/cmp/RCCL/RCCLabout.html). Treatment of melanoma cells with PLX4032 or cytotoxic anti-cancer drugs had been shown to result in the selection of ABCB5-expressing cells [25]. However, we did not detect enhanced ABCB5 expression in our resistance models relative to the parental sensitive cells.Figure 3

Bottom Line: 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.PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion.Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.

View Article: PubMed Central - PubMed

Affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str, 40, Frankfurt am Main 60596, Germany. Cinatl@em.uni-frankfurt.de.

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.

Show MeSH
Related in: MedlinePlus