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- Title
Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors.
- Authors
Basile, Kevin J.; Le, Kaitlyn; Hartsough, Edward J.; Aplin, Andrew E.
- Abstract
Vemurafenib and dabrafenib block MEK- ERK1/2 signaling and cause tumor regression in the majority of advanced-stage BRAFV600E melanoma patients; however, acquired resistance and paradoxical signaling have driven efforts for more potent and selective RAF inhibitors. Next-generation RAF inhibitors, such as PLX7904 ( PB04), effectively inhibit RAF signaling in BRAFV600E melanoma cells without paradoxical effects in wild-type cells. Furthermore, PLX7904 blocks the growth of vemurafenib-resistant BRAFV600E 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 PLX7904 and its clinical analog, PLX8394 ( PB03), in BRAFV600E splice variant-mediated vemurafenib-resistant cells. We show that paradox-breaker RAF inhibitors potently block MEK- ERK1/2 signaling, G1/S cell cycle events, survival and growth of vemurafenib/ PLX4720-resistant cells harboring distinct BRAFV600E 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.
- Subjects
ENZYME inhibitors; TUMOR growth; TREATMENT duration; MELANOMA; NEUROENDOCRINE tumors; PATIENTS; CANCER risk factors
- Publication
Pigment Cell & Melanoma Research, 2014, Vol 27, Issue 3, p479
- ISSN
1755-1471
- Publication type
Article
- DOI
10.1111/pcmr.12218