Doan Hung Q, Chen Leon, Nawas Zeena, Lee Heng-Huan, Silapunt Sirunya, Migden Michael
Department of Dermatology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Dermatology, University of Texas McGovern Medical School, Houston, TX, USA.
Oncotarget. 2021 Sep 28;12(20):2089-2100. doi: 10.18632/oncotarget.28080.
Although basal cell carcinoma (BCC) is often managed successfully with surgery, patients with locally advanced BCC (laBCC) or metastatic BCC (mBCC) who are not candidates for surgery or radiotherapy have limited treatment options. Most BCCs result from aberrant Hedgehog pathway activation in keratinocyte tumor cells, caused by sporadic or inherited mutations. Mutations in the patched homologue 1 gene that remove its inhibitory regulation of Smoothened homologue (SMO) or mutations in that make it constitutively active, lead to Hedgehog pathway dysregulation and downstream activation of GLI1/2 transcription factors, promoting cell differentiation and proliferation. Hedgehog inhibitors (HHIs) block overactive signaling of this pathway by inhibiting SMO and are currently the only approved treatments for advanced BCC. Two small-molecule SMO inhibitors, vismodegib and sonidegib, have shown efficacy and safety in clinical trials of advanced BCC patients. Although these agents are effective and tolerable for many patients, HHI resistance occurs in some patients. Mechanisms of resistance include mutations in SMO, noncanonical cell identity switching leading to tumor cell resistance, and non-canonical pathway crosstalk causing Hedgehog pathway activation. Approaches to managing HHI resistance include switching HHIs, HHI and radiotherapy combination therapy, photodynamic therapy, and targeting Hedgehog pathway downstream effectors. Increasing understanding of the control of downstream effectors has identified new therapy targets and potential agents for evaluation in BCC. Identification of biomarkers of resistance or response is needed to optimize HHI use in patients with advanced BCC. This review examines HHI resistance, its underlying mechanisms, and methods of management for patients with advanced BCC.
尽管基底细胞癌（BCC）通常通过手术治疗成功，但局部晚期基底细胞癌（laBCC）或转移性基底细胞癌（mBCC）患者若不适合手术或放疗，其治疗选择有限。大多数基底细胞癌是由散发性或遗传性突变导致角质形成细胞肿瘤细胞中异常的Hedgehog信号通路激活引起的。patched同源物1基因的突变消除了其对Smoothened同源物（SMO）的抑制调节，或者使SMO组成型激活的基因突变，导致Hedgehog信号通路失调和GLI1/2转录因子的下游激活，促进细胞分化和增殖。Hedgehog抑制剂（HHIs）通过抑制SMO来阻断该通路的过度活跃信号，目前是晚期基底细胞癌唯一获批的治疗方法。两种小分子SMO抑制剂，维莫德吉和索尼德吉，在晚期基底细胞癌患者的临床试验中已显示出疗效和安全性。尽管这些药物对许多患者有效且耐受性良好，但一些患者会出现HHI耐药。耐药机制包括SMO突变、导致肿瘤细胞耐药的非经典细胞身份转换以及导致Hedgehog信号通路激活的非经典通路串扰。管理HHI耐药的方法包括更换HHIs、HHI与放疗联合治疗、光动力疗法以及靶向Hedgehog信号通路的下游效应器。对下游效应器控制的深入了解已确定了新的治疗靶点和用于基底细胞癌评估的潜在药物。需要鉴定耐药或反应的生物标志物，以优化晚期基底细胞癌患者的HHI使用。本综述探讨了HHI耐药、其潜在机制以及晚期基底细胞癌患者的管理方法。
