Department of Molecular Oncology, Genentech, San Francisco, CA, USA.
Department of Bioinformatics and Computational Biology, Genentech, San Francisco, CA, USA.
Nature. 2018 Oct;562(7727):429-433. doi: 10.1038/s41586-018-0596-y. Epub 2018 Oct 8.
Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC), residual disease persists in some patients and may contribute to relapse when treatment is discontinued. Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1-Trp53 mouse model of BCC and found that mice treated with vismodegib harbour quiescent residual tumours that regrow upon cessation of treatment. Profiling experiments revealed that residual BCCs initiate a transcriptional program that closely resembles that of stem cells of the interfollicular epidermis and isthmus, whereas untreated BCCs are more similar to the hair follicle bulge. This cell identity switch was enabled by a mostly permissive chromatin state accompanied by rapid Wnt pathway activation and reprogramming of super enhancers to drive activation of key transcription factors involved in cellular identity. Accordingly, treatment of BCC with both vismodegib and a Wnt pathway inhibitor reduced the residual tumour burden and enhanced differentiation. Our study identifies a resistance mechanism in which tumour cells evade treatment by adopting an alternative identity that does not rely on the original oncogenic driver for survival.
尽管 Hedgehog 通路抑制剂在治疗基底细胞癌（BCC）方面具有疗效，但在一些患者中仍存在残留疾病，并且在停止治疗时可能导致复发。在这里，为了研究 Smoothened 抑制剂维莫德吉对肿瘤清除的影响，我们使用了 Ptch1-Trp53 小鼠 BCC 模型，发现用维莫德吉治疗的小鼠存在静止的残留肿瘤，在停止治疗后会重新生长。分析实验表明，残留的 BCC 启动了一个转录程序，与滤泡间表皮和峡部的干细胞非常相似，而未经治疗的 BCC 则更类似于毛囊隆起。这种细胞身份转换是由一种主要允许的染色质状态、快速的 Wnt 通路激活以及超级增强子的重编程所驱动的，以激活参与细胞身份的关键转录因子。因此，用维莫德吉和 Wnt 通路抑制剂联合治疗 BCC 可减少残留肿瘤负担并增强分化。我们的研究确定了一种耐药机制，其中肿瘤细胞通过采用不依赖原始致癌驱动因素生存的替代身份来逃避治疗。
