Discovery of a tumour cell population responsible for resistance to therapy and tumour relapse in the most frequent human cancer.

Researchers lead by Pr. Cédric Blanpain, MD/PhD, WELBIO investigator and Professor at the Université Libre de Bruxelles, Belgium, identified a population of tumour cells that persist following drug treatment, leading to cancer relapse following treatment discontinuation in basal cell carcinoma, the most frequent skin cancer. The study also identifies a combination of drugs that can eliminate the tumour population that resists to the therapy and prevents tumour relapse after treatment discontinuation. The results of this study have been published in Nature.

De nombreux patients traités avec vismodegib (médicament approuvé par la FDA (Food and Drug Administration) pour le traitement des carcinomes basocellulaires localement avancés et métastatiques) présentent une régression tumorale au cours du traitement ; mais très fréquemment, ils présentent une rechute de leur tumeur après l’arrêt de celui-ci. Les mécanismes par lesquels le vismodegib induit une régression tumorale et comment les cellules tumorales résistent à la thérapie et conduisent à la rechute du cancer restent mal compris.

Many patients treated with Vismodegib (a FDA approved drug) experience tumour regression during treatment, but very often their tumours relapse following treatment discontinuation. The precise mechanisms involved in tumour regression upon Vismodegib administration and how the tumour cells resist to the therapy leading to cancer relapse are poorly understood.

In this new study, researchers identified the mechanism by which Vismodegib leads to tumour regression and uncovered the origin of the relapse observed upon treatment discontinuation. They found that Vismodegib promotes the differentiation of the bulk of tumour cells, leading to their elimination. Vismodegib treatment led to the emergence of a population of dormant tumour cells characterized by active Wnt signaling that persists despite continuous drug administration. In collaboration with the groups of Pr. Tabernero (Vall d’Hebron Institute of Oncology, Barcelona, Spain) and Pr. del Marmol (Hôpital Erasme, Brussels, Belgium), the researchers demonstrated that this population of tumour cells presenting active Wnt signaling was also found in patients with basal cell carcinoma treated with Vismodegib.

Adriana Sánchez-Danés and colleagues found that inhibition of Wnt signaling together with Vismodegib eliminates the persisting tumour lesions, leading to tumour eradication in the vast majority of the cases. “It was really exciting to identify a combination of drugs already available in clinics that led to the eradication of resisting tumour cells and avoided tumour relapse in the most frequent cancer in humans”, comments Adriana Sánchez-Danés, the first author of the study.

Altogether, this study illustrates that Vismodegib promotes tumour regression by promoting the differentiation of tumour cells. This demonstrates for the first time that inducing tumour differentiation is a safe and efficient strategy to treat solid tumours such as basal cell carcinoma. “This is the first example of a FDA approved drug used to treat solid tumours that induces tumour regression through differentiation. Tumour differentiation is an exciting route to treat cancer, as it is non toxic for normal cells and was proved to be a revolutionary treatment in certain leukemia”, said Cédric Blanpain, the senior author of study. “Our study also identifies a new mechanism of resistance to therapy in basal cell carcinoma and demonstrates that the administration of two existing drugs is sufficient to prevent tumour relapse in the vast majority of the cases. The next step would be to conduct clinical trials using the combination of these two drugs in patients with relapsing basal cell carcinomas and possibly other cancers characterised by the activation of the two signaling pathways identified here”, explains Cédric Blanpain, the corresponding author of the Nature paper.

References : Adriana Sánchez-Danés et al. (2018) A slow cycling Lgr5 tumour population mediates basal cell carcinoma relapse after therapy. Nature. doi10.1038/s41586-018-0603-3

Last update : 9/10/2018 - Vie privée - Printable version -  © 2019 WELBIO

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