A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells

authors

• Arfaoui Abir
• Rioualen Claire
• Azzoni Violette
• Pinna Guillaume
• Finetti Pascal
• Wicinski Julien
• Josselin Emmanuelle
• Macario Manon
• Castellano Rémy
• Léonard-Stumpf Candi
• Bal Anthony
• Gros Abigaelle
• Lossy Sylvain
• Kharrat Maher
• Collette Yves
• Bertucci François
• Birnbaum Daniel
• Douik Hayet
• Bidaut Ghislain
• Charafe-Jauffret Emmanuelle
• Ginestier Christophe

keywords

• Regenerative Medicine
• Chemical Biology
• Breast cancer
• JQ1
• Cancer stem cells
• Salinomycin
• RNAi screen

abstract

Therapeutic resistance is a major clinical challenge in oncology. Evidence identifies cancer stem cells (CSCs) as a driver of tumor evolution. Accordingly, the key stemness property unique to CSCs may represent a reservoir of therapeutic target to improve cancer treatment. Here, we carried out a genome-wide RNA interference screen to identify genes that regulate breast CSCs-fate (bCSC). Using an interactome/regulome analysis, we integrated screen results in a functional mapping of the CSC-related processes. This network analysis uncovered potential therapeutic targets controlling bCSC-fate. We tested a panel of 15 compounds targeting these regulators. We showed that mifepristone, salinomycin, and JQ1 represent the best anti-bCSC activity. A combination assay revealed a synergistic interaction of salinomycin/JQ1 association to deplete the bCSC population. Treatment of primary breast cancer xenografts with this combination reduced the tumor-initiating cell population and limited metastatic development. The clinical relevance of our findings was reinforced by an association between the expression of the bCSC-related networks and patient prognosis. Targeting bCSCs with salinomycin/JQ1 combination provides the basis for a new therapeutic approach in the treatment of breast cancer.

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