Driving toward targeted therapy for LCH

Abstract

In this issue of Blood, Brown et al identify somatic mutations of MAP2K1 capable of driving the RAS-RAF-MEK-ERK pathway in Langerhans cell histiocytosis (LCH). Their findings lend important insight into the pathogenesis of this disease and provide the rationale for exploring targeted approaches in clinical trials.

The RAS-RAF-MEK-ERK pathway represents a driver in the pathogenesis of LCH while offering the potential for targeted therapeutic approaches. As much as 60% of LCH patients carry mutated forms of ARAF or BRAF (V600E) capable of constitutive phosphorylation of the downstream effectors MEK1 and MEK2 that ultimately drive ERK activity. Up to 50% BRAF-V600E–negative LCH cases (27% total) harbor a mutation in MAP2K1 that leads to constitutive MEK1 and consequent ERK activation, promoting downstream proliferation and survival networks to drive LCH. The mutually exclusive presence of BRAF and MAP2K1 mutations presents an ideal opportunity to intervene with selective agents like vemurafenib or trametinib to target 2 critical enzymes essential to LCH pathogenesis.