title: Inhibition of mutant BRAF splice variant signaling by next-generation, selective RAF 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.
authors.affiliation: Department of Cancer Biology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Basile
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Le
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hartsough
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000235:genetics; D011905:Genes, ras; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D000077484:Vemurafenib; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D007211:Indoles; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D010091:Oximes; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C561627:dabrafenib
keywords: BRAF; Paradox-breaker RAF inhibitor; splice variant; vemurafenib resistance