Department of Dermatology, Mayo Clinic College of Medicine and Science, Onalaska, WI, USA.
Division of Hematology and Oncology, Department of Internal Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Am J Clin Dermatol. 2018 Apr;19(2):195-207. doi: 10.1007/s40257-017-0319-4.
Basal cell carcinoma (BCC) is the most common type of skin cancer, with rising incidence rates primarily attributed to an aging population and ultraviolet radiation exposure. While the majority of BCCs are localized and respond to standard therapies, a very small minority of these tumors become locally destructive or metastasize. These advanced BCCs may not be amenable to localized treatment with surgery and/or radiation therapy. Most BCCs result from mutations in key receptors in the Hedgehog (HH) signaling pathway. As a result, identification of drugs that inhibit the receptor Smoothened (SMO) in the HH pathway has resulted in novel therapeutic approaches to treating patients with advanced BCC. These HH-pathway inhibiting medications have shown efficacy in clinical trials, and two medications, vismodegib and sonidegib, have received FDA approval. However, several limitations of these drugs have been identified, including treatment-limiting adverse events, drug resistance, and the formation of additional malignancies. This paper aims to summarize the clinical trials leading to the approval of SMO inhibitors, as well as reviewing potential mechanisms driving tumor resistance and the formation of cutaneous squamous cell carcinomas. Strategies to overcome some of these challenges, including the development of drugs that inhibit other downstream targets in the HH pathway, are the subject of ongoing clinical trials.
基底细胞癌（BCC）是最常见的皮肤癌类型，发病率上升主要归因于人口老龄化和紫外线辐射暴露。虽然大多数 BCC 局限于局部区域并对标准疗法有反应，但这些肿瘤中极少数会变得局部破坏性或转移。这些晚期 BCC 可能不适用于手术和/或放射疗法的局部治疗。大多数 BCC 是由于 Hedgehog（HH）信号通路中的关键受体发生突变引起的。因此，鉴定抑制 HH 通路中受体 Smoothened（SMO）的药物已导致治疗晚期 BCC 患者的新治疗方法。这些 HH 通路抑制药物在临床试验中显示出疗效，两种药物，即维莫德吉和索尼德吉，已获得 FDA 批准。然而，已经确定了这些药物的几个局限性，包括治疗受限的不良反应、耐药性和形成额外的恶性肿瘤。本文旨在总结导致 SMO 抑制剂批准的临床试验，并回顾驱动肿瘤耐药性和形成皮肤鳞状细胞癌的潜在机制。克服其中一些挑战的策略，包括开发抑制 HH 通路中其他下游靶标的药物，是正在进行的临床试验的主题。
