A(nother) RAF mutation in LCH

Abstract

In this issue of Blood, Nelson et al describe a novel somatic ARAF mutation in a child with Langerhans cell histiocytosis (LCH) and demonstrate that the encoded protein has strong gain-of-function properties. Importantly, this mutant A-Raf molecule is sensitive to inhibition by vemurafenib, a potent and selective Raf kinase inhibitor that is Food and Drug Administration (FDA)-approved for the treatment of advanced melanoma. This work thus identifies a new driver mutation in LCH that is potentially actionable in the clinic.

Ras accumulates in the active GTP-bound conformation in response to growth factor stimulation and other extracellular stimuli. Normal Raf proteins bind to Ras-GTP and signal as homo- and heterodimers. BRAF and ARAF mutations found in LCH and other cancers exhibit constitutive kinase activation, which results in the sequential activation of MEK and ERK. Vemurafenib and trametinib are potent and selective inhibitors of Raf and MEK, respectively.