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PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells
Article first published online: 10 FEB 2010
© 2010 John Wiley & Sons A/S
Pigment Cell & Melanoma Research
Volume 23, Issue 2, pages 190–200, April 2010
How to Cite
Halaban, R., Zhang, W., Bacchiocchi, A., Cheng, E., Parisi, F., Ariyan, S., Krauthammer, M., McCusker, J. P., Kluger, Y. and Sznol, M. (2010), PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells. Pigment Cell & Melanoma Research, 23: 190–200. doi: 10.1111/j.1755-148X.2010.00685.x
- Issue published online: 10 MAR 2010
- Article first published online: 10 FEB 2010
- PUBLICATION DATA Received 2 February 2010, revised and accepted for publication 5 February 2010, published online 10 February 2010
- cell migration;
- drug response;
- ERK pathway;
- serum markers
BRAFV600E/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 BRAFV600E/K and BRAFWT showed that, paradoxically, while PLX4032 inhibited ERK1/2 in the highly sensitive BRAFV600E/K, it activated the pathway in the resistant BRAFWT cells, via RAF1 activation, regardless of the status of mutations in NRAS or PTEN. The persistently active ERK1/2 triggered downstream effectors in BRAFWT 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 BRAFWT primary and metastatic tumor cells in vivo and provide markers for monitoring clinical responses.