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PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells.
- Source :
- Pigment Cell & Melanoma Research; Apr2010, Vol. 23 Issue 2, p190-200, 11p, 3 Diagrams, 1 Chart, 3 Graphs
- Publication Year :
- 2010
-
Abstract
- BRAF<superscript>V600E/K</superscript> is a frequent mutationally active tumor-specific kinase in melanomas that is currently targeted for therapy by the specific inhibitor PLX4032. Our studies with melanoma tumor cells that are BRAF<superscript>V600E/K</superscript> and BRAF<superscript>WT</superscript> showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAF<superscript>V600E/K</superscript>, it activated the pathway in the resistant BRAF<superscript>WT</superscript> cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK1/2 triggered downstream effectors in BRAF<superscript>WT</superscript> melanoma cells and induced changes in the expression of a wide-spectrum of genes associated with cell cycle control. Furthermore, PLX4032 increased the rate of proliferation of growth factor-dependent NRAS Q61L mutant primary melanoma cells, reduced cell adherence and increased mobility of cells from advanced lesions. The results suggest that the drug can confer an advantage to BRAF<superscript>WT</superscript> primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses. [ABSTRACT FROM AUTHOR]
- Subjects :
- CELL migration
GENETIC mutation
MELANOMA
GENES
METASTASIS
CANCER cells
Subjects
Details
- Language :
- English
- ISSN :
- 17551471
- Volume :
- 23
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Pigment Cell & Melanoma Research
- Publication Type :
- Academic Journal
- Accession number :
- 48489546
- Full Text :
- https://doi.org/10.1111/j.1755-148X.2010.00685.x