Chapter 22 - Targeting the RAS-RAF-MEK-ERK Signaling Pathway in Gliomas

Abstract

p21-RAS is a small guanine-nucleotide (GTP) binding protein that is mutated in 33% of human cancers. RAS signaling regulates an array of cellular functions such as cell growth, survival, and differentiation through the activation of downstream signaling pathways, the best studied being the RAS-RAF-MEK-ERK pathway. Activated GTP-bound RAS binds to and activates RAF, a serine–threonine kinase that phosphorylates and activates the dual specificity protein kinases MEK, triggering the MEK/ERK phosphorylation cascade. Alterations within the RAS-RAF-MEK-ERK pathway have recently been characterized in gliomas due to advancements in whole genome and transcriptome analysis with some surprising results. Activating mutations in RAS were considered rare or even absent in gliomas until a recent study identified a substantial number of KRAS and NRAS mutations in diffuse gliomas (Ceccarelli et al., 2016). Frequent mutations and alterations within the RAS signaling pathway, including NF1 mutations and deletions, BRAF-V600E mutations, and BRAF fusions, have been identified in sporadic gliomas. Targeting RAS signaling in melanomas has demonstrated dramatic results and shows promise in clinical studies in gliomas. Continued investigation of RAS signaling in gliomas will be critical for the development of future therapies, which will help in treating this disease that otherwise has a very dismal prognosis.