Despite the efficacy of Hedgehog pathway inhibitors in the treatment of basal cell carcinoma (BCC)1, residual disease persists in some patients and may contribute to relapse when treatment is discontinued2. Here, to study the effect of the Smoothened inhibitor vismodegib on tumour clearance, we have used a Ptch1–Trp53 mouse model of BCC3 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.When basal cell carcinoma is treated with a Smoothened inhibitor, a subset of cancer cells evades treatment by switching identity, allowing residual tumours to regrow when treatment is discontinued.

中文翻译：

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细胞身份转换允许残留的 BCC 在 Hedgehog 通路抑制中存活

尽管 Hedgehog 通路抑制剂在治疗基底细胞癌 (BCC)1 中有效，但残留疾病在某些患者中持续存在，并且在停止治疗时可能会导致复发2。在这里，为了研究 Smoothened 抑制剂 vismodegib 对肿瘤清除率的影响，我们使用了 BCC3 的 Ptch1-Trp53 小鼠模型，发现用 vismodegib 治疗的小鼠具有静止的残留肿瘤，这些肿瘤在停止治疗后会重新生长。分析实验表明，残留的 BCC 启动转录程序，该程序与毛囊间表皮和峡部的干细胞非常相似，而未经处理的 BCC 更类似于毛囊隆起。这种细胞身份转换是由主要允许的染色质状态实现的，伴随着快速的 Wnt 途径激活和超级增强子的重编程，以驱动参与细胞身份的关键转录因子的激活。因此，用 vismodegib 和 Wnt 通路抑制剂治疗 BCC 减少了残留的肿瘤负荷并增强了分化。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于原始致癌驱动因素的替代身份来逃避治疗。当基底细胞癌用平滑抑制剂治疗时，一部分癌细胞通过转换身份逃避治疗，当停止治疗时，允许残留的肿瘤重新生长。用 vismodegib 和 Wnt 通路抑制剂治疗 BCC 减少了残留的肿瘤负荷并增强了分化。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于原始致癌驱动因素的替代身份来逃避治疗。当基底细胞癌用平滑抑制剂治疗时，一部分癌细胞通过转换身份逃避治疗，当停止治疗时，允许残留的肿瘤重新生长。用 vismodegib 和 Wnt 通路抑制剂治疗 BCC 减少了残留的肿瘤负荷并增强了分化。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于原始致癌驱动因素的替代身份来逃避治疗。当基底细胞癌用平滑抑制剂治疗时，一部分癌细胞通过转换身份逃避治疗，当停止治疗时，允许残留的肿瘤重新生长。