Abstract
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.
Highlights
Epithelial ovarian cancers (EOC) are the leading cause of death from gynecologic cancer
D, IGROV1-R10 cancer cells were transfected with indicated miRNA and caspase-3/7 green apoptosis assay reagent was added
To decipher the mechanisms underlying the apoptotic effect of miR-3622b-5p in ovarian cancer cells lines, we focused on ERBB2 and EGFR [29]
Summary
Epithelial ovarian cancers (EOC) are the leading cause of death from gynecologic cancer. More than 230,000 new cases are diagnosed each year worldwide leading to the death of about 140,000 women [1]. The current first-line treatment for patients with EOC consists of cytoreductive surgery and platinum-based chemotherapy [2, 3]. Despite a good primary chemotherapy response, the majority of patients with EOC will relapse and develop platinum resistance, explaining the poor 5-year survival rate below 30% for advanced FIGO (International Federation of Gynecologists and Obstetricians) stages The development of novel and effective therapies is critical for improving EOC outcome. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)
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