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Inhibition of mutant BRAF splice variant signaling by next‐generation, selective RAF inhibitors
Author(s) -
Basile Kevin J.,
Le Kaitlyn,
Hartsough Edward J.,
Aplin Andrew E.
Publication year - 2014
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.12218
Subject(s) - vemurafenib , dabrafenib , neuroblastoma ras viral oncogene homolog , cancer research , trametinib , mapk/erk pathway , melanoma , signal transduction , mutation , medicine , biology , kras , microbiology and biotechnology , genetics , gene , metastatic melanoma
Summary Vemurafenib and dabrafenib block MEK ‐ ERK 1/2 signaling and cause tumor regression in the majority of advanced‐stage BRAF V 600E melanoma patients; however, acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors. Next‐generation RAF inhibitors, such as PLX 7904 ( PB 04), effectively inhibit RAF signaling in BRAF V 600E melanoma cells without paradoxical effects in wild‐type cells. Furthermore, PLX 7904 blocks the growth of vemurafenib‐resistant BRAF V 600E cells that express mutant NRAS . Acquired resistance to vemurafenib and dabrafenib is also frequently driven by expression of mutation BRAF splice variants; thus, we tested the effects of PLX 7904 and its clinical analog, PLX 8394 ( PB 03), in BRAF V 600E splice variant‐mediated vemurafenib‐resistant cells. We show that paradox‐breaker RAF inhibitors potently block MEK ‐ ERK 1/2 signaling, G1/S cell cycle events, survival and growth of vemurafenib/ PLX 4720‐resistant cells harboring distinct BRAF V 600E splice variants. These data support the further investigation of paradox‐breaker RAF inhibitors as a second‐line treatment option for patients failing on vemurafenib or dabrafenib.