Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific raf inhibitor PLX4032

Jonas Nørskov Søndergaard, R. Nazarian, Q. Wang, D. Guo, T. Hsueh, S. Mok, H. Sazegar, L. E. Macconail, J. G. Barretina, S.M. Kehoe, N. Attar, E. von Euw, J.E. Zuckerman, B. Chmielowski, B. Comin-Anduix, R. C. Koya, P. S. Mischel, R. S. Lo, A. J. Ribas

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    Abstract

    Blocking oncogenic signaling induced by the BRAFV600E mutation is a promising approach for melanoma treatment. We tested the anti-tumor effects of a specific inhibitor of Raf protein kinases, PLX4032/RG7204, in melanoma cell lines. PLX4032 decreased signaling through the MAPK pathway only in cell lines with the BRAFV600E mutation. Seven out of 10 BRAFV600E mutant cell lines displayed sensitivity based on cell viability assays and three were resistant at concentrations up to 10 muM. Among the sensitive cell lines, four were highly sensitive with IC50 values below 1 muM, and three were moderately sensitive with IC50 values between 1 and 10 muM. There was evidence of MAPK pathway inhibition and cell cycle arrest in both sensitive and resistant cell lines. Genomic analysis by sequencing, genotyping of close to 400 oncogeninc mutations by mass spectrometry, and SNP arrays demonstrated no major differences in BRAF locus amplification or in other oncogenic events between sensitive and resistant cell lines. However, metabolic tracer uptake studies demonstrated that sensitive cell lines had a more profound inhibition of FDG uptake upon exposure to PLX4032 than resistant cell lines. In conclusion, BRAFV600E mutant melanoma cell lines displayed a range of sensitivities to PLX4032 and metabolic imaging using PET probes can be used to assess sensitivity.
    Original languageEnglish
    JournalJournal of Translational Medicine
    Volume8
    ISSN1479-5876
    DOIs
    Publication statusPublished - 2010

    Bibliographical note

    This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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