Langerhans cell histiocytosis: molecular mechanisms underlying pathogenesis and emerging targeted therapeutics.

Langerhans cell histiocytosis (LCH) is a nonhereditary myeloid neoplasm driven by somatic alterations in the mitogen-activated protein kinase (MAPK) signaling pathway, most commonly involving BRAF and MAP2K1 (MEK1). Oncogenic BRAF alterations activate MAPK signaling through diverse structural mechanisms. The prominent BRAF(V600E) mutation traps BRAF in a constitutively active status by forming the K507-E600 salt bridge independent of upstream RAS signaling. In contrast, non-V600E BRAF mutants exhibit variable kinase activity, among which kinase-dead variants rely on BRAF/CRAF heterodimerization and transactivate CRAF. In parallel, oncogenic MEK1 mutations disrupt autoinhibition or enhance MEK1 homodimerization, sustaining MAPK activation. Furthermore, RAF/MEK heterodimerization modulates pathway output and persistence. These mechanistic insights provide a strong biological rationale for therapeutic targeting of the MAPK pathway in LCH, thereby driving the clinical use of BRAF inhibitors (BRAFi) including vemurafenib and dabrafenib, as well as MEK inhibitors (MEKi) such as trametinib and cobimetinib. However, the efficacy is frequently limited by acquired resistance associated with MAPK pathway reactivation through RAF and MEK dimerization-dependent mechanisms. Collectively, these altered molecular interactions contribute to the pathway dysregulation and signaling persistence, thereby providing a mechanistic basis for adaptive resistance and for developing next-generation RAFi and MEKi. This review therefore summarizes the current understanding of the molecular mechanisms underlying MAPK pathway activation and therapeutic resistance in LCH, with particular emphasis on conformational switch-based regulations of RAF and MEK proteins, and discusses emerging strategies involving next-generation RAFi and RAFi plus MEKi combinations aimed to achieve more durable MAPK pathway suppression and improving long-term outcomes of LCH treatment.