A slow-cycling Lgr5 tumour population mediates basal cell carcinoma relapse after therapy

Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway1. Several Smoothened inhibitors (Smoi) are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma2. Vismodegib, a Smoi, leads to BCC shrinkage in the majority of the BCC patients3, but the mechanism by which it mediates BCC regression is currently unknown. Here, we used two different genetically engineered mouse models4 to investigate the mechanisms by which Smoi mediates tumor regression. We found that vismodegib mediates BCCs regression by inhibiting hair follicle-like fate and promoting the differentiation of tumour cells (TCs). However, a small population of TCs persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans5. In both mouse and human BCC, this persisting slow-cycling tumour population expresses Lgr5 and is characterised by active Wnt signalling. Lgr5 lineage ablation or Wnt signalling inhibition together with vismodegib leads to BCC eradication. Our study reveals that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors constitutes a clinically relevant strategy to overcome tumour relapse in BCC.