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A slow cycling Lgr5 tumor cell population mediates resistance to Smoothened inhibitor in Basal Cell Carcinoma

Adriana, Sánchez-Danés and Jean-Christophe , Larsimont and Mélanie, Liagre and Eva , Muñoz and Audrey, Brisebarre and Christine, Dubois and Josep, Tabernero and Cédric , Blanpain (2018) A slow cycling Lgr5 tumor cell population mediates resistance to Smoothened inhibitor in Basal Cell Carcinoma. Nature. ISSN 1476-4687

Abstract

Basal cell carcinoma (BCC) is the most common human cancer. Smoothened inhibitor (Smoi) is used for the treatment of locally advanced and metastatic BCC. The mechanism by which Smoi mediates BCC regression is currently unknown. Here, we used two different genetically engineered mouse models to investigate the mechanisms by which Smoi mediates tumor regression. We found that Smoi mediates BCC regression by inhibiting their reprogramming into hair follicle like fate and promoting their differentiation towards interfollicular epidermis, infundibulum and sebaceous gland fates depending on their cellular origin. During the course of Smoi administration, some BCC became resistant to therapy mimicking the situation found in humans. We demonstrated that the resistant tumor cells express Lgr5 and were characterized by active Wnt signalling in mouse and human BCCs. Smoi in combination with Lgr5 lineage ablation or Wnt signalling inhibition leads to BCC eradication. Altogether, our study reveals that Smoi induces tumor regression by promoting tumor differentiation, and demonstrates that the synergy between Wnt and Smo inhibitors constitutes a clinically relevant strategy to overcome resistance to therapy in BCCs.

Item Type: Article
Date Deposited: 25 Oct 2018 00:45
Last Modified: 25 Oct 2018 00:45
URI: https://oak.novartis.com/id/eprint/33481

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