Functional miRNA Screening Identifies Wide-ranging Antitumor Properties of miR-3622b-5p and Reveals a New Therapeutic Combination Strategy in Ovarian Tumor Organoids

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 patientderived 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.

The role of patient-derived ovarian cancer organoids in the study of PARP inhibitors sensitivity and resistance: from genomic analysis to functional testing

“…Chen et al developed short duration organoid cultures of multicellular spheroids (MCSs) from ovarian cancer malignant effusions and used them as a platform for empirical drug sensitivity testing [113]. In addition, there are also some preclinical studies that utilized PDOs as a disease model to verify the newly discovered molecular mechanisms and targeting strategies in different subtypes of ovarian cancer [117][118][119][120][121][122].…”

Network-Based Integration of Multi-Omics Data Identifies the Determinants of miR-491-5p Effects

“…We postulated that mimicking the effects of a miRNA using drugs already available or easily amenable to clinical practice would constitute a valuable proxy for the clinical use of miRNAs. We previously showed that miR-491-5p [9] and miR-3622b-5p [10] directly target Bcl-xL and EGFR in ovarian cancer cells, and that the combined use of Bcl-xL and EGFR inhibitors, respectively, in clinical trials (ABT-263), which are FDA-approved for the treatment of non-small-cell lung cancer (gefitinib), could efficiently recapitulate the cytotoxicity induced by both of these miRNAs. Although positive, the results of this previous study did bear two drawbacks.…”

“…But despite numerous still ongoing clinical trials, the current limitations for the clinical use of nucleic acids-such as siRNAs, miRNAs or anti-miRNAs-have undermined such strategies to date [8]. However, understanding the determinants of the cytotoxic phenotype triggered by a given miRNA might enable the identification of druggable targets and thus, the design of innovative therapeutic strategies aiming to mimic its effects [9,10]. Ovarian cancer constitutes the leading cause of death from gynecological malignancies in developed countries, with a low 5-year survival rate of less than 40% [11].…”

“…We chose to use miR-491-5p as a model system because it appeared among the top hits for its cytotoxic effects, in the IGROV1-R10 chemoresistant cell line in a screen of a library of 1233 miRNAs [10]. Moreover, some of the most significant targets mediating its cytotoxic effects in ovarian cancer cells are already identified [9].…”

Therapeutic advances of miRNAs: A preclinical and clinical update

“…It has been noted that miR-3622b-5p augment apoptosis and also sensitizes cells to cisplatin. Therefore, this miRNA can be used for the chemotherapy combined therapeutic approach for the treatment of cancer [111] . Thus, miRNA therapeutics might help counteract drug resistance issues in the near future.…”