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; KIAA1549-BRAF 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.
Introduction
The characterization of the genomic landscape of primary brain tumors has enhanced the understanding of the molecular pathways involved in tumorigenesis (Behling et al., 2016; Schindler et al., 2011). Development of targeted treatments for brain tumors has accumulated increased interest in recent decades (Staedtke et al., 2016). Mutations in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene were identified in large-scale sequencing of tumors and are more commonly found in malignant melanomas, papillary thyroid carcinomas, and colorectal carcinomas, and less frequently in non-small cell lung carcinoma (NSCLC), ovarian carcinomas, hairy cell leukemia, and primary brain tumors (Davies et al., 2002). BRAF protein, a member of the RAF family of serine/threonine kinases, participates in the cascade of the Ras-Raf-MEK-extracellular signal-regulated kinase (ERK) pathway or mitogen-activated protein kinase (MAPK)/ERK signaling pathway that affects cell division and differentiation (Matallanas et al., 2011). BRAF inhibitors (BRAFi) received U.S. Food and Drug Administration (FDA) approval for the treatment of malignancies with BRAF-V600E mutations such as metastatic or unresectable melanoma, NSCLC, and Erdheim-Chester disease (Chapman et al., 2011; Diamond et al., 2018; Hauschild et al., 2012; Planchard et al., 2016). Understanding of the role of BRAF in tumorigenesis of primary brain tumors has facilitated the design of clinical trials with MAPK/ERK pathway inhibitors that are currently underway (NCT01748149, NCT01677741, NCT01748149, NCT01677741, NCT02684058, NCT03363217). Novel treatments for brain tumors are an unmet need for improving the overall survival of these patients. The focus of this review is to explore the role of BRAF aberrations in the development of primary brain tumors, and to summarize the reports of adult primary brain tumor treatments with BRAFi and other inhibitors of the Ras-Raf-MEK-ERK pathway.
