Relief of Profound Feedback Inhibition of Mitogenic Signaling by RAF Inhibitors Attenuates Their Activity in BRAFV600E Melanomas
Menée in vitro et in vivo, cette étude suggère l'intérêt d'un traitement combinant un inhibiteur de MEK et un inhibiteur de RAF dans les mélanomes présentant la mutation V600E du gène BRAF
BRAFV600E drives tumors by dysregulating ERK signaling. In these tumors, we show that high levels of ERK-dependent negative feedback potently suppress ligand-dependent mitogenic signaling and Ras function. BRAFV600E activation is Ras independent and it signals as a RAF-inhibitor-sensitive monomer. RAF inhibitors potently inhibit RAF monomers and ERK signaling, causing relief of ERK-dependent feedback, reactivation of ligand-dependent signal transduction, increased Ras-GTP, and generation of RAF-inhibitor-resistant RAF dimers. This results in a rebound in ERK activity and culminates in a new steady state, wherein ERK signaling is elevated compared to its initial nadir after RAF inhibition. In this state, ERK signaling is RAF inhibitor resistant, and MEK inhibitor sensitive, and combined inhibition results in enhancement of ERK pathway inhibition and antitumor activity. º BRAFV600E signals as a RAF-inhibitor-sensitive monomer º RAF inhibitors alleviate ERK-dependent feedback and reactivate mitogenic signaling º RAF inhibitors cause increased Ras-GTP, leading to inhibitor-resistant RAF dimers º Combining RAF and MEK inhibitors enhanced ERK inhibition and antitumor activity