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PLX4032, a selective BRAF V600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF WT melanoma cells
Author(s) -
Halaban Ruth,
Zhang Wengeng,
Bacchiocchi Antonella,
Cheng Elaine,
Parisi Fabio,
Ariyan Stephan,
Krauthammer Michael,
McCusker James P.,
Kluger Yuval,
Sznol Mario
Publication year - 2010
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2010.00685.x
Subject(s) - neuroblastoma ras viral oncogene homolog , melanoma , cancer research , pten , mapk/erk pathway , cell growth , vemurafenib , kinase , biology , chemistry , microbiology and biotechnology , signal transduction , pi3k/akt/mtor pathway , mutation , metastatic melanoma , gene , biochemistry , kras
Summary 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.