Molecular mechanisms of gefitinib-induced rash formation: Gefitinib augments lipogenesis and steroidgenesis in sebaceous glands

吉非替尼是一种靶向表皮生长因子受体配体结合域的小分子酪氨酸激酶抑制剂，在晚期非小细胞肺癌患者中显示出抗肿瘤活性。许多接受吉非替尼治疗的患者在面部和上半身出现痤疮样皮疹。虽然痤疮被认为是皮脂腺和毛囊皮脂腺单位的功能障碍，但迄今为止还没有吉非替尼可以调节皮脂腺皮脂产生的报道。在目前的研究中，质谱分析显示，口服吉非替尼的患者在接受吉非替尼治疗的脓疱中可检测到，但在四名痤疮患者的脓疱中未检测到。此外，吉非替尼增加了人类和仓鼠脂细胞中主要皮脂成分甘油三酯（TG）和脂细胞分化标记物perilippin的产生。此外，吉非替尼促进了仓鼠和人脂细胞的类固醇生成。因此，这些结果提供了新的证据，证明吉非替尼口服后存在于皮肤毛囊中，并通过增加TG的产生直接促进皮脂的产生。此外，皮脂生成的增加可能是由于皮脂细胞中雄激素合成的增加。这些发现将有助于增加临床对吉非替尼副作用的认识，提高吉非替尼治疗患者的生活质量

A small-molecule tyrosine kinase inhibitor, gefitinib, which targets the ligand-binding domain of epidermal growth factor receptors, exhibits anti-tumorigenic activity in patients with advanced non-small cell lung cancer. Many patients treated with gefitinib develop an acne-like rash on the face and upper body. Although acne is characterized as a functional disorder in sebaceous glands and pilosebaceous units, there have been no reports to date that gefitinib may modulate sebum production in sebaceous glands. In the present study, a mass spectrometry analysis revealed that orally administrated gefitinib was detectable in a pustule from a patient treated with gefitinib but not ones from four acne patients. In addition, gefitinib augmented the production of triacylglycerols (TG), the major sebum component, and perilipin, a sebocytic differentiation marker, in human and hamster sebocytes. Furthermore, gefitinib facilitated steroidogenesis in both hamster and human sebocytes. Therefore, these results provide novel evidence that gefitinib exists in the hair follicle of the skin after its oral administration and directly facilitates sebum production by the augmentation of TG production. Moreover, the augmentation of sebum production is likely to due to the increases of androgen synthesisin sebocytes. These findings will help to increase the clinical understanding of the side effects of gefitinib, and improve the QOL of patients being treated with gefitinib