Immunological Effects of BRAF/MEK Inhibitors in Malignant Melanoma

Abstract

BRAF/MEK inhibitors have shown great therapeutic potential for treating patients with malignant melanomas harboring BRAF mutations. Unfortunately, administration of these inhibitors often leads to systemic inflammation, fever, and elevated C-reactive protein (CRP) levels. We retrospectively examined dynamic changes in CRP levels and white blood cell counts in patients with malignant melanoma treated with BRAF/MEK inhibitors, who initially displayed significantly elevated CRP levels and neutrophil and lymphocyte counts. We also analyzed changes in mRNA levels in healthy human and mouse lymphocytes treated with MEK inhibitors alone or BRAF/MEK inhibitors. We found that genes related to IL-6 were elevated in both murine and human lymphocytes, while TNF-α mRNA levels unexpectedly decreased. Furthermore, CXCL16, GADD45B, and PIK3CG levels were elevated in all mouse and human groups. These findings suggest that BRAF/MEK inhibitors may elicit inflammation, denoted by elevated CRP levels, and that the changes in expression of IL-6 pathway genes observed in in vitro experiments with mouse and human lymphocytes may trigger this inflammation.