Inhibition of mutant BRAF splice variant signaling by next generation, selective RAF inhibitors
Menée sur des lignées cellulaires de mélanome résistantes au vemurafenib et au dabrafenib, cette étude évalue l'activité antitumorale de composés représentant une nouvelle génération d'inhibiteurs de RAF (PLX7904 et PLX8394)
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. This article is protected by copyright. All rights reserved.