TY - JOUR
T1 - Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032
AU - Søndergaard, Jonas N.
AU - Nazarian, Ramin
AU - Wang, Qi
AU - Guo, Deliang
AU - Hsueh, Teli
AU - Mok, Stephen
AU - Sazegar, Hooman
AU - MacConaill, Laura E.
AU - Barretina, Jordi G.
AU - Kehoe, Sarah M.
AU - Attar, Narsis
AU - von Euw, Erika
AU - Zuckerman, Jonathan E.
AU - Chmielowski, Bartosz
AU - Comin-Anduix, Begoña
AU - Koya, Richard C.
AU - Mischel, Paul S.
AU - Lo, Roger S.
AU - Ribas, Antoni
N1 - Funding Information:
We would like to thank Dr. Gideon Bollag from Plexxikon for providing PLX4032 and for helpful discussions regarding these studies. We would also like to thank Drs. William Tap and Dennis Slamon at UCLA, and Peter Hirth at Plexxikon for helpful discussions. This work was funded in part by the Jonsson Cancer Center Foundation (JCCF), the NIH award P50 CA086306 and by the Caltech-UCLA Joint Center for Translational Medicine (to AR); and the Dermatology Foundation, the STOP CANCER Foundation and the Burroughs Welcome Fund (to RSL).
PY - 2010/4/20
Y1 - 2010/4/20
N2 - Blocking oncogenic signaling induced by the BRAFV600Emutation 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.
AB - Blocking oncogenic signaling induced by the BRAFV600Emutation 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.
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U2 - 10.1186/1479-5876-8-39
DO - 10.1186/1479-5876-8-39
M3 - Article
C2 - 20406486
AN - SCOPUS:77950954465
SN - 1479-5876
VL - 8
JO - Journal of translational medicine
JF - Journal of translational medicine
M1 - 39
ER -