PDF(Pubmed)
Abstract：
Although basal cell carcinomas arise from ectopic Hedgehog pathway activation and can be treated with pathway inhibitors, sporadic basal cell carcinomas display high resistance rates, whereas tumors arising in patients with Gorlin syndrome with germline Patched (PTCH1) alterations are uniformly suppressed by inhibitor therapy. In rare cases, patients with Gorlin syndrome on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. In this study, we report a case of an SMO inhibitor-resistant tumor arising in a patient with Gorlin syndrome on suppressive SMO inhibitor for nearly a decade. Using a combination of multiomics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMO inhibitors through the previously described basal to squamous cell carcinoma transition. Intriguingly, through spatial whole-exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as genetic suppressors of basal to squamous cell carcinoma transition resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMO inhibitors for not only Gorlin syndrome but also sporadic basal cell carcinomas.
摘要：
虽然基底细胞癌（BCC）是由异位hedgehog通路激活引起的，可以用通路抑制剂治疗，散发性BCCs表现出很高的耐药率,而在具有种系Patched(PTCH1)突变的Gorlin综合征患者中出现的肿瘤被抑制剂治疗一致抑制.在极少数情况下,接受长期抑制剂治疗的Gorlin综合征患者会发展出快速发展的单个耐药肿瘤克隆，但是这种抵抗的基础仍未研究。在这里，我们报告了Gorlin患者在抑制性SMOi中出现的SMOi耐药肿瘤近十年的病例。使用多组学和空间转录组学的组合，我们在细胞和组织水平定义了肿瘤群体,从而得出结论,Gorlin肿瘤可以通过先前描述的基底细胞癌过渡到鳞状细胞癌(BST)对SMOi产生耐药性.有趣的是，通过空间全外显子组基因组分析，我们提名PCYT2，ETNK1和磷脂酰乙醇胺生物合成途径为BST抗性的遗传抑制因子。这些观察结果为研究肿瘤演变提供了一般框架，并为不仅Gorlin综合征而且散发性BCC对SMOi的耐药机制提供了重要的临床见解。
