1. Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF inhibitors.
- Author
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Basile KJ, Le K, Hartsough EJ, and Aplin AE
- Subjects
- Cell Cycle drug effects, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Enzyme Activation drug effects, GTP Phosphohydrolases antagonists & inhibitors, GTP Phosphohydrolases genetics, Genes, ras, Humans, Imidazoles pharmacology, Indoles pharmacology, MAP Kinase Signaling System drug effects, Melanoma pathology, Membrane Proteins antagonists & inhibitors, Membrane Proteins genetics, Mutation, Missense, Neoplasm Proteins genetics, Oximes pharmacology, Phosphorylation drug effects, Protein Isoforms antagonists & inhibitors, Protein Processing, Post-Translational drug effects, Proto-Oncogene Proteins B-raf genetics, Signal Transduction drug effects, Sulfonamides pharmacology, Tumor Stem Cell Assay, Vemurafenib, Melanoma enzymology, Neoplasm Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf antagonists & inhibitors, raf Kinases antagonists & inhibitors
- Abstract
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., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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