Differential Sensitivity of Melanoma Cell Lines with BRAFV600E Mutation to the Specific Raf Inhibitor PLX4032

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Differential Sensitivity of Melanoma Cell Lines with BRAFV600E Mutation to the Specific Raf Inhibitor PLX4032

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Title: Differential Sensitivity of Melanoma Cell Lines with BRAFV600E Mutation to the Specific Raf Inhibitor PLX4032
Author: Søndergaard, Jonas N; Nazarian, Ramin; Guo, Deliang; Hsueh, Teli; Mok, Stephen; Sazegar, Hooman; Barretina, Jordi G; Kehoe, Sarah M; Attar, Narsis; von Euw, Erika; Zuckerman, Jonathan E; Chmielowski, Bartosz; Comin-Anduix, Begoña; Koya, Richard C; Mischel, Paul S; Lo, Roger S; Ribas, Antoni; Wang, Qi; MacConaill, Laura Eleanor

Note: Order does not necessarily reflect citation order of authors.

Citation: Søndergaard, Jonas N., Ramin Nazarian, Qi Wang, Deliang Guo, Teli Hsueh, Stephen Mok, Hooman Sazegar, et al. 2010. Differential sensitivity of melanoma cell lines with mutation to the specific Raf inhibitor PLX4032. Journal of Translational Medicine 8: 39.
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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 μM. Among the sensitive cell lines, four were highly sensitive with IC50 values below 1 μM, and three were moderately sensitive with IC50 values between 1 and 10 μM. 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.
Published Version: doi:10.1186/1479-5876-8-39
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876068/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:4706594

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