Differential sensitivity of melanoma cell lines with BRAF V600E mutation to the specific Raf inhibitor PLX4032

Jonas Nørskov Søndergaard(University of California, Los Angeles), Ramin Nazarian(University of California, Los Angeles), Qi Wang(University of California, Los Angeles), Deliang Guo(University of California, Los Angeles), Teli Hsueh(University of California, Los Angeles), Stephen Mok(University of California, Los Angeles), Hooman Sazegar(University of California, Los Angeles), Laura E. MacConaill(Broad Institute), Jordi Barretina(Broad Institute), Sarah M. Kehoe(Broad Institute), Narsis Attar(University of California, Los Angeles), Erika von Euw(University of California, Los Angeles), Jonathan E. Zuckerman(University of California, Los Angeles), Bartosz Chmielowski(University of California, Los Angeles), Begoña Comı́n-Anduix(University of California, Los Angeles), Richard C. Koya(University of California, Los Angeles), Paul S. Mischel(University of California, Los Angeles), Roger S. Lo(University of California, Los Angeles), Antoni Ribas(University of California, Los Angeles)
Journal of Translational Medicine
April 20, 2010
10.1186/1479-5876-8-39
Cited by 227Open Access
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Abstract

Abstract Blocking oncogenic signaling induced by the BRAF V600E 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 BRAF V600E mutation. Seven out of 10 BRAF V600E 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 IC 50 values below 1 μM, and three were moderately sensitive with IC 50 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, BRAF V600E mutant melanoma cell lines displayed a range of sensitivities to PLX4032 and metabolic imaging using PET probes can be used to assess sensitivity.

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