BRAF and MEK inhibitors in pediatric glioma: new therapeutic strategies, new toxicities

Introduction: BRAF mutation was initially reported in metastatic melanomas, and more recently in a variety of human cancers. BRAF acts as a down-stream effector of growth factor signaling leading to cell cycle progression, proliferation and survival. Development of selective inhibitors of BRAF has improved the survival of patients with melanoma and offers potential new therapeutic strategy in children with BRAF-mutant glioma. Areas covered: Mechanisms of resistance to BRAF inhibitors have recently been described as due to the paradoxical activation of the MAPK pathway. Combination therapy with BRAF and MEK inhibition has proved capable of overcoming the resistance with effective results in patients with melanoma. Prospective studies in pediatric glioma are warranted. Combination therapy has a different toxicity profile compared to BRAF inhibitor alone. Herein we review the state-of-the-art of toxicities associated with these agents, with a special focus on children. Expert opinion: Some toxicities appear more specific to adults, due to a combination of factors, such as patient age and predisposing risk factors. Moreover, it is recommended that the co-administration of BRAF inhibitors and drugs metabolized by the cytochrome P450 system in the liver be avoided, as this can lead to significant complications secondary to pharmacological interactions.