696 MEK and BRAF inhibitors augment the production and accumulation of sebum in hamster sebocytes

Abstract

The activation of RAS-RAF-MEK-ERK signal pathway has been associated with tumor progression. Selective MEK and BRAF protein kinase inhibitors, trametinib and vemurafenib, respectively, exhibit anti-tumorigenic activity in patients with metastatic melanoma. Many patients treated with trametinib or vemurafenib develop common adverse events such as acne-like rash. Although acne is characterized as a functional disorder in sebaceous glands and pilosebaceous units, e.g., excess sebum production, secretion, and accumulation, there have been no reports to date that trametinib and vemurafenib may modulate sebum production in sebaceous glands. In the present study, therefore, we examined whether or not trametinib and vemurafenib directly influenced the sebum production in hamster sebocytes (HamSEB) in vitro. Intracellular lipid-droplet formation was augmented by trametinib and vemurafenib in HamSEB. In addition, both trametinib and vemurafenib were found to increase the production of triacylglycerols (TG), a major component of sebum, in HamSEB. Furthermore, the gene expression of diacylglycerol acyltransferase-1 (DGAT-1) and perilipin-1, which participate in sebum production and accumulation, respectively, was found to be augmented by both reagents. Thus, trametinib and vemurafenib are likely to directly facilitate sebum production and accumulation along with the increased expression of DGAT-1 and perilipin in HamSEB. These findings may increase the clinical understanding of the side effects of trametinib and vemurafenib.