RT Journal Article
SR Electronic
T1 Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 1506
OP 1519
DO 10.1158/1535-7163.MCT-19-0510
VO 19
IS 7
A1 Vernon, Mégane
A1 Lambert, Bernard
A1 Meryet-Figuière, Matthieu
A1 Brotin, Emilie
A1 Weiswald, Louis-Bastien
A1 Paysant, Hippolyte
A1 Vigneron, Nicolas
A1 Wambecke, Anaïs
A1 Abeilard, Edwige
A1 Giffard, Florence
A1 Louis, Marie-Hélène
A1 Blanc-Fournier, Cécile
A1 Gauduchon, Pascal
A1 Poulain, Laurent
A1 Denoyelle, Christophe
YR 2020
UL http://mct.aacrjournals.org/content/19/7/1506.abstract
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