A genome‐wide RNA i 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 Francois
  • Birnbaum Daniel
  • Douik Hayet
  • Bidaut Ghislain
  • Charafe-Jauffret Emmanuelle
  • Ginestier Christophe
  • Léonard‐stumpf Candi
  • Charafe‐jauffret Emmanuelle

keywords

  • Breast cancer
  • RNAi screen
  • JQ1
  • Salinomycin
  • Cancer stem cells

document type

ART

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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