BRAF Inhibitors for the Treatment of Papulopustular Eruptions from MAPK Pathway Inhibitors.

Abstract

Inhibitors of the mitogen-activated protein kinase (MAPK) pathway are commonly used in clinical oncology. However, with the exception of BRAF inhibitors (BRAFi), MAPK pathway inhibitors such as epidermal growth factor receptor inhibitors (EGFRi) or MEK inhibitors (MEKi) are associated with dose-limiting papulopustular eruptions. Interestingly, patients treated with a combination of systemic BRAFi and MEKi experience less skin toxicities than patients on monotherapy BRAFi or MEKi. The reduction in cutaneous adverse events with combination therapy is thought to be due to a paradoxical activation of the MAPK pathway by BRAFi in keratinocytes carrying wildtype BRAF. Although treatment options for EGFRi- or MEKi-induced papulopustular eruptions exist, many patients still experience dose reduction, interruption, or discontinuation of EGFRi or MEKi. With the goal of activating MAPK signaling in the skin via BRAFi while minimizing systemic risks, we propose topical BRAFi therapy for the treatment and prevention of papulopustular eruptions due to MAPK pathway inhibitors. If effective, patients will be able to tolerate higher doses of MAPK pathway inhibitors, stay on treatment longer, and achieve better therapeutic outcomes overall.