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PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells.
- Source :
-
Pigment cell & melanoma research [Pigment Cell Melanoma Res] 2010 Apr; Vol. 23 (2), pp. 190-200. Date of Electronic Publication: 2010 Feb 10. - Publication Year :
- 2010
-
Abstract
- BRAF(V600E/K) 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(V600E/K) and BRAF(WT) showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAF(V600E/K), it activated the pathway in the resistant BRAF(WT) cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK1/2 triggered downstream effectors in BRAF(WT) 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(WT) primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses.
- Subjects :
- Cell Proliferation drug effects
Dose-Response Relationship, Drug
Humans
Indoles adverse effects
Melanoma drug therapy
Melanoma enzymology
Melanoma genetics
Mitogen-Activated Protein Kinase 1 antagonists & inhibitors
Mitogen-Activated Protein Kinase 3 antagonists & inhibitors
Protein Kinase Inhibitors adverse effects
Structure-Activity Relationship
Sulfonamides adverse effects
Vemurafenib
Cell Movement drug effects
Indoles pharmacology
Melanoma pathology
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins B-raf antagonists & inhibitors
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1755-148X
- Volume :
- 23
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Pigment cell & melanoma research
- Publication Type :
- Academic Journal
- Accession number :
- 20149136
- Full Text :
- https://doi.org/10.1111/j.1755-148X.2010.00685.x