Study identifies tumor cell population responsible for resistance to therapy and cancer relapse

Resistance to therapy is a major problem in cancer patients as the cells that resist to therapy is at the root of tumor relapse and is associated with high morbidity and mortality. A better understanding of the mechanisms associated with resistance to therapy is essential for the development of better strategies to definitively eradicate cancer and prevent tumor relapse.

In a study published in Nature, researchers lead by Pr. Cédric Blanpain, MD/PhD, WELBIO investigator and Professor at the Université libre de Bruxelles, Belgium identified a population of tumor 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 this the tumor population that resists to the therapy and prevents tumor relapse after treatment discontinuation.

Basal cell carcinoma is the most common human cancer, affecting several millions of new patients each year across the world. Vismodegib, a FDA approved drug is used for the treatment of locally advanced and metastatic basal cell carcinoma in humans. Many patients treated with vismodegib experience tumor regression during treatment, but very often their tumors relapse following treatment discontinuation. The precise mechanisms involved in tumor regression upon vismodegib administration and how the tumor cells resist to the therapy leading to cancer relapse are poorly understood.

In this new study, Adriana Sánchez-Danés - Université libre de Bruxelles, ULB, Laboratory of Stem Cells and Cancer - and colleagues identified the mechanism by which vismodegib leads to tumor regression and uncovered the origin of the relapse observed upon treatment discontinuation. They found that vismodegib promotes the differentiation of the bulk of tumor cells, leading to their elimination. Vismodegib treatment led to the emergence of population of dormant tumor cells characterized by active Wnt signaling that persists despite continuous drug administration.

In collaboration with the groups of Pr. Tabernero (Barcelona, Spain) and Pr. del Marmol (Brussels, Belgium), the researchers demonstrated that this population of tumor cell population active for 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 tumor lesions leading to tumor eradication in the vast majority of the cases. "It was really exciting to identify a combination of drugs already available in clinics that lead to the eradication of resisting tumor cells and avoiding tumor 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 tumor regression by promoting the differentiation of tumor cells. This demonstrates for the first time that inducing tumor differentiation is a safe and efficient strategy to treat solid tumors such as basal cell carcinoma. "This is the first example of a FDA approved drug used to treat solid tumor that induces tumor regression through differentiation. Tumor 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. &laquo 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 tumor 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 characterized by the activation of the two signaling pathways identified here", explains Cédric Blanpain, the corresponding author of the Nature paper.

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