The activation of the RAS-RAF-MEK-ERK signal pathway has been associated with tumor progression. A selective BRAF protein kinase inhibitor, vemurafenib, exhibits anti-tumorigenic activity in patients with metastatic melanoma. However, adverse reactions such as an acne-like rash and dry skin appear in patients treated with vemurafenib. Such cutaneous disorders have been associated with the dysfunction of sebaceous glands and pilosebaceous units, allowing us to speculate that vemurafenib may influence sebum production in sebaceous glands. In the present study, we demonstrated that vemurafenib enhanced the production of triacylglycerol (TG), a major component in sebum, in insulin-differentiated hamster sebocytes (HamSeb). In addition, vemurafenib was found to increase the gene expression of stearoyl-CoA desaturase 1 (SCD1) in insulin-differentiated HamSeb. However, vemurafenib was also found to suppress 5a-dihydrotestosterone (5α-DHT)-induced TG production and SCD1 mRNA expression in HamSeb. Regarding the molecular mechanism(s) of the bidirectional regulation of TG production, both insulin and 5a-DHT activated the signal pathway of mTOR, which is a pivotal mediator for sebaceous lipogenesis in HamSeb. In addition, an mTOR inhibitor, KU0063794, inhibited both insulin- and 5α-DHT-augmented TG production. Furthermore, vemurafenib-augmented TG production was decreased by KU0063794 in insulin-differentiated HamSeb　and vemurafenib-suppressed TG production was also decreased by KU0063794 in 5a-DHT-treated HamSeb. Therefore, these results suggest that vemurafenib bidirectionally regulates sebum production dependent on sebogenesis factor species, leading to adverse reactions such as an acne-like rash and dry skin. Furthermore, the side effects of vemurafenib may be associated with the activation of the mTOR pathway in HamSeb.

Vemurafenib, a BRAF inhibitor, bidirectionally regulates sebum production through an mTOR pathway in differentiated hamster sebocytes