Targeting Ras-RAF-ERK and its Interactive Pathways as a Novel Therapy for Malignant Gliomas

Malignant gliomas are the most common and the deadliest brain malignancies in adults. Despite the lack of a complete understanding of the biology of these tumors, significant advances have been made in the past decades. One of the key discoveries made in the area of malignant gliomas is that these tumors can be induced and maintained by aberrant signaling networks. In this context, the Ras pathway has been extensively exploited, from both basic and translational perspectives. Although somatic oncogenic mutations of Ras genes are frequent in several cancer types, early investigations on gliomas revealed disappointing facts that the Ras mutations are nearly absent in malignant gliomas and that the BRAF mutations are present in a very small percentage of gliomas. Therefore, the observed deregulation of the Ras-RAF-ERK signaling pathway in gliomas is attributed to its upstream positive regulators, including, EGFR and PDGFR known to be highly active in the majority of malignant gliomas. In contrast to the initial negative results on the somatic mutations of H-Ras, K-Ras and BRAF, recent breakthrough studies on pediatric low-grade astrocytomas uncovered genetic alterations of the BRAF gene involving copy number gains and rearrangements. The 7q34 rearrangements result in a novel in-frame KIAA1549:BRAF fusion gene that possesses constitutive BRAF kinase activity resembling oncogenic BRAF (V600E). In light of the earlier findings and recent breakthroughs, this review summarizes our current understanding of the Ras-RAF-ERK signaling pathway in gliomas and the outcome of preclinical and clinical studies that evaluated the efficacy of Ras-targeted therapy in malignant gliomas.