期刊
PIGMENT CELL & MELANOMA RESEARCH
卷 27, 期 3, 页码 479-484出版社
WILEY-BLACKWELL
DOI: 10.1111/pcmr.12218
关键词
BRAF; Paradox-breaker RAF inhibitor; splice variant; vemurafenib resistance
资金
- National Institutes of Health [CA160495]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Joanna M. Nicolay Melanoma Foundation
- National Cancer Center
- National Cancer Institute [P30CA56036]
Vemurafenib and dabrafenib block MEK-ERK1/2 signaling and cause tumor regression in the majority of advanced-stage BRAF(V600E) 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 BRAF(V600E) melanoma cells without paradoxical effects in wild-type cells. Furthermore, PLX7904 blocks the growth of vemurafenib-resistant BRAF(V600E) 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 BRAF(V600E) 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 BRAF(V600E) 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.
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