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

Abir Arfaoui (1, 2) , Claire Rioualen (1) , Violette Azzoni (1) , Guillaume Pinna (3, 4) , Pascal Finetti (1) , Julien Wicinski (1) , Emmanuelle Josselin (1) , Manon Macario (1) , Rémy Castellano (1) , Candi Léonard-Stumpf (1) , Anthony Bal (1) , Abigaelle Gros (1) , Sylvain Lossy (5) , Maher Kharrat (2) , Yves Collette (6) , François Bertucci (6) , Daniel Birnbaum (1) , Hayet Douik (7, 2) , Ghislain Bidaut (1) , Emmanuelle Charafe-Jauffret (1) , Christophe Ginestier (1)

1 CRCM - Centre de Recherche en Cancérologie de Marseille
2 UTM - Université de Tunis El Manar
3 I2BC - Institut de Biologie Intégrative de la Cellule
4 PARI - PARi
5 SBIGeM - Service de Biologie Intégrative et Génétique Moléculaire
6 IPC - Institut Paoli-Calmettes
7 Institut Salah Azaiz

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.

Mots clés: Regenerative Medicine; Chemical Biology; breast cancer; JQ1; cancer stem cells; salinomycin; RNAi screen

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]

Abir Arfaoui, Claire Rioualen, Violette Azzoni, Guillaume Pinna, Pascal Finetti, et al.. A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells. EMBO Molecular Medicine, 2019, 11 (10), pp.e9930. ⟨10.15252/emmm.201809930⟩. ⟨hal-02539524⟩