TY - JOUR
T1 - The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations
AU - Comin-Anduix, Begoña
AU - Chodon, Thinle
AU - Sazegar, Hooman
AU - Matsunaga, Douglas
AU - Mock, Stephen
AU - Jalil, Jason
AU - Escuin-Ordinas, Helena
AU - Chmielowski, Bartosz
AU - Koya, Richard C.
AU - Ribas, Antoni
PY - 2010/12/15
Y1 - 2010/12/15
N2 - Purpose: PLX4032 (RG7204), an oncogenic BRAF kinase inhibitor undergoing clinical evaluation, has high response rates in early clinical trials in patients with advanced BRAFV600E mutant melanoma. Combining PLX4032 with immunotherapy may allow expanding the durability of responses. The effects of PLX4032 on immune cells were studied to explore the feasibility of future combinatorial approaches with immunotherapy for melanoma. Experimental Design: Peripheral blood mononuclear cells (PBMC) and BRAFV600E mutant melanoma cells were exposed to increasing concentrations of PLX4032 and the cell viability, proliferation, cell cycle, apoptosis, and phosphorylation of signaling proteins were analyzed. Effects of PLX4032 on antigenspecific T-cell function were analyzed by specific cytokine release and cytotoxicity activity. Results: The 50% inhibition concentration (IC50) of PLX4032 for resting human PBMC was between 50 and 150 μmol/L compared with an IC 50 below 1 μmol/L for sensitive BRAFV600E mutant melanoma cell lines. Activated lymphocytes were even more resistant with no growth inhibition up to concentrations of 250 μmol/L. PLX4032 had a marginal effect on cell-cycle arrest, apoptotic cell changes or alteration of phosphorylated signaling molecules in lymphocytes. Functional analysis of specific antigen recognition showed preserved T-cell function up to 10-μmol/L concentration of PLX4032, whereas the cytotoxic activity of PLX4032 was maintained up to high concentrations of 50 μmol/L. Conclusions: The preserved viability and function of lymphocytes exposed to high concentrations of PLX4032 suggest that this agent could be a potential candidate for combining with immunotherapy strategies for the treatment of patients with BRAFV600E mutant melanoma.
AB - Purpose: PLX4032 (RG7204), an oncogenic BRAF kinase inhibitor undergoing clinical evaluation, has high response rates in early clinical trials in patients with advanced BRAFV600E mutant melanoma. Combining PLX4032 with immunotherapy may allow expanding the durability of responses. The effects of PLX4032 on immune cells were studied to explore the feasibility of future combinatorial approaches with immunotherapy for melanoma. Experimental Design: Peripheral blood mononuclear cells (PBMC) and BRAFV600E mutant melanoma cells were exposed to increasing concentrations of PLX4032 and the cell viability, proliferation, cell cycle, apoptosis, and phosphorylation of signaling proteins were analyzed. Effects of PLX4032 on antigenspecific T-cell function were analyzed by specific cytokine release and cytotoxicity activity. Results: The 50% inhibition concentration (IC50) of PLX4032 for resting human PBMC was between 50 and 150 μmol/L compared with an IC 50 below 1 μmol/L for sensitive BRAFV600E mutant melanoma cell lines. Activated lymphocytes were even more resistant with no growth inhibition up to concentrations of 250 μmol/L. PLX4032 had a marginal effect on cell-cycle arrest, apoptotic cell changes or alteration of phosphorylated signaling molecules in lymphocytes. Functional analysis of specific antigen recognition showed preserved T-cell function up to 10-μmol/L concentration of PLX4032, whereas the cytotoxic activity of PLX4032 was maintained up to high concentrations of 50 μmol/L. Conclusions: The preserved viability and function of lymphocytes exposed to high concentrations of PLX4032 suggest that this agent could be a potential candidate for combining with immunotherapy strategies for the treatment of patients with BRAFV600E mutant melanoma.
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U2 - 10.1158/1078-0432.CCR-10-1911
DO - 10.1158/1078-0432.CCR-10-1911
M3 - Article
C2 - 21169256
AN - SCOPUS:78650391890
SN - 1078-0432
VL - 16
SP - 6040
EP - 6048
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -