BRAF alterations in primary brain tumors

Abstract

Primary brain tumors can harbor v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene alterations. BRAF is a serine/threonine kinase protein and is a downstream effector of the Ras-Raf-MEK extracellular signal-regulated kinase (ERK) signaling pathway, which is responsible for cell division and differentiation. BRAF-V600E mutations are most commonly found in pleomorphic xanthoastrocytoma, ganglioglioma, epithelioid glioblastoma, and gliomas diagnosed at a younger age; BRAF-KIAA1549 fusion is the most common BRAF alteration in pilocytic astrocytoma. First-generation BRAF inhibitors (BRAFi) have shown effectiveness in the treatment of melanoma patients with brain metastases and are currently undergoing clinical trials for the treatment of pediatric primary brain tumors with the BRAF-V600E mutation. Numerous case reports in adult primary brain tumors with BRAF-V600E mutations demonstrate signals of BRAFi activity in the brain. BRAFi are commonly combined with other inhibitors of the Ras-Raf-MEK-ERK pathway for the avoidance of BRAFi resistance, while second-generation BRAFi have been developed with safer side-effect profiles and decreased resistance. Primary brain tumors with KIAA1549-BRAF fusion should not be treated with first-generation BRAFi due to paradoxical activation of the Ras-Raf-MEK-ERK pathway.