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Selective RAF inhibitor impairs ERK 1/2 phosphorylation and growth in mutant NRAS , vemurafenib‐resistant melanoma cells
Author(s) -
Le Kaitlyn,
Blomain Erik S.,
Rodeck Ulrich,
Aplin Andrew E.
Publication year - 2013
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/pcmr.12092
Subject(s) - vemurafenib , neuroblastoma ras viral oncogene homolog , melanoma , cancer research , phosphorylation , mapk/erk pathway , mutant , mek inhibitor , mutation , apoptosis , biology , kras , microbiology and biotechnology , biochemistry , metastatic melanoma , gene
Summary The RAF inhibitor vemurafenib achieves remarkable clinical responses in mutant BRAF melanoma patients. However, vemurafenib is burdened by acquired drug resistance and by the side effects associated with its paradoxical activation of the ERK 1/2 pathway in wild‐type BRAF cells. This paradoxical effect has driven the development of a new class of RAF inhibitors. Here, we tested one of these selective, non‐paradox‐inducing RAF inhibitors termed paradox‐breaker‐04 ( PB 04) or PLX 7904. Consistent with its design, PB 04 is able to efficiently inhibit activation of ERK 1/2 in mutant BRAF melanoma cells but does not hyperactivate ERK 1/2 in mutant RAS ‐expressing cells. Importantly, PB 04 inhibited ERK 1/2 phosphorylation in mutant BRAF melanoma cells with acquired resistance to vemurafenib/ PLX 4720 that is mediated by a secondary mutation in NRAS . Consistent with ERK 1/2 reactivation driving the re‐acquisition of malignant properties, PB 04 promoted apoptosis and inhibited entry into S phase and anchorage‐independent growth in mutant N ‐ RAS ‐mediated vemurafenib‐resistant cells. These data indicate that paradox‐breaker RAF inhibitors may be clinically effective as a second‐line option in a cohort of acquired vemurafenib‐resistant patients.