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

ABSTRACT

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.

KEYWORDS:

• BRAF inhibitors
• pediatric glioma
• MEK inhibitors
• toxicity

Article highlights

• BRAFV600E mutation results in the constitutive activation of BRAFV600E, affecting cell proliferation, differentiation, and survival.

• Recent studies have identified BRAF mutations in childhood cancers, and in particular in pediatric glioma, with a different incidence in different histotypes.

• BRAF inhibitors have also been successfully used in patients with BRAF-mutant glioma.

• Mechanisms of resistance to treatment with BRAF inhibitors have recently been observed.

• Resistance mechanisms reactivate the MAPK pathway; therefore, inhibition of the MAPK pathway at two nodes, combining both a BRAF inhibitor and a MEK inhibitor, has been tested.

• New drugs have a different toxicity profile compared to conventional chemotherapy.

• The toxicities in children may be different compared to adults due to a combination of factors, such as patient age and predisposing risk factors.

• Skin toxicities are the most common adverse events associated with BRAF and MEK inhibitors.

• The combination of BRAF and MEK inhibitors has been shown to significantly alleviate the paradoxical activation of MAPK and to reduce the skin toxicity found using a BRAF inhibitor alone; however, addition of the MEK inhibitor adds other toxicities, such as pyrexia, gastrointestinal and ocular toxicity.

• Before starting BRAF inhibitors it is important to perform dermatologic and ophthalmological examination, electrocardiogram (ECG), measurement of blood pressure, serum electrolytes, and liver function evaluation. Close follow up during and after treatment is recommended.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.