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

小分子酪氨酸激酶抑制剂吉非替尼针对表皮生长因子受体的配体结合区域，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粉刺样皮疹。尽管痤疮是皮脂腺和毛皮脂腺单位的一种功能性疾病，但到目前为止还没有关于吉非替尼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的脓肿中可以检测到服用吉非替尼的患者，但不能从4名痤疮患者的脓疮中检测到吉非替尼。此外，吉非替尼增加了人和仓鼠皮脂细胞中三酰甘油(TG)和Perilipin的产生，三酰甘油是皮脂的主要成分，Perilipin是皮脂细胞分化的标志。此外，吉非替尼促进了仓鼠和人类皮脂细胞中类固醇的合成。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的毛囊中，并通过促进甘油三酯的产生直接促进皮脂的产生。此外，皮脂产量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了解，并改善接受吉非替尼治疗的患者的生活质量。

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