PT  - JOURNAL ARTICLE
AU  - Vernon, Mégane
AU  - Lambert, Bernard
AU  - Meryet-Figuière, Matthieu
AU  - Brotin, Emilie
AU  - Weiswald, Louis-Bastien
AU  - Paysant, Hippolyte
AU  - Vigneron, Nicolas
AU  - Wambecke, Anaïs
AU  - Abeilard, Edwige
AU  - Giffard, Florence
AU  - Louis, Marie-Hélène
AU  - Blanc-Fournier, Cécile
AU  - Gauduchon, Pascal
AU  - Poulain, Laurent
AU  - Denoyelle, Christophe
TI  - Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids
AID  - 10.1158/1535-7163.MCT-19-0510
DP  - 2020 Jul 01
TA  - Molecular Cancer Therapeutics
PG  - 1506--1519
VI  - 19
IP  - 7
4099  - http://mct.aacrjournals.org/content/19/7/1506.short
4100  - http://mct.aacrjournals.org/content/19/7/1506.full
SO  - Mol Cancer Ther2020 Jul 01; 19
AB  - Novel therapeutic strategies are urgently required for the clinical management of chemoresistant ovarian carcinoma, which is the most lethal of the gynecologic malignancies. miRNAs hold promise because they play a critical role in determining the cell phenotype by regulating several hundreds of targets, which could constitute vulnerabilities of cancer cells. A combination of gain-of-function miRNA screening and real-time continuous cell monitoring allows the identification of miRNAs with robust cytotoxic effects in chemoresistant ovarian cancer cells. Focusing on miR-3622b-5p, we show that it induces apoptosis in several ovarian cancer cell lines by both directly targeting Bcl-xL and EGFR-mediating BIM upregulation. miR-3622b-5p also sensitizes cells to cisplatin by inhibiting Bcl-xL in ovarian cancer cell lines escaping BIM induction. miR-3622b-5p also exerts antimigratory capacities by targeting both LIMK1 and NOTCH1. These wide-ranging antitumor properties of miR-3622b-5p in ovarian cancer cells are mimicked by the associations of pharmacologic inhibitors targeting these proteins. The combination of an EGFR inhibitor together with a BH3-mimetic molecule induced a large decrease in cell viability in a panel of ovarian cancer cell lines and several ovarian patient-derived tumor organoids, suggesting the value of pursuing such a combination therapy in ovarian carcinoma. Altogether, our work highlights the potential of phenotype-based miRNA screening approaches to identify lethal interactions which might lead to new drug combinations and clinically applicable strategies.This article is featured in Highlights of This Issue, p. 1383