ハムスター脂腺細胞におけるBRAF阻害剤であるベムラフェニブの脂腺障害発症の分子機構

抄録

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 this study, we demonstrated that vemurafenib enhanced the production of triacylglycerol (TG), a major component in sebum, in insulin-differentiated hamster sebocytes (HamSeb). However, vemurafenib suppressed 5α-dihydrotestosterone (5α-DHT)-induced TG production in HamSeb. Regarding the molecular mechanism(s) of the bidirectional regulation of TG production, both insulin and 5α-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, whereas there was no change in the vemurafenib-suppressed TG production in 5α-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 sebaceous glands.