The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells.

Abstract

Simple SummaryThe current standard therapy of ovarian cancers comprises a reductive surgery followed by a combination of taxane-platinum-based primary chemotherapy. However, despite an initial positive response, patients in the advanced stage showed relapse within months or even weeks. Thus, there is a need to find combinatorial therapies that permit overcoming the paclitaxel-associated resistance in patients. Here, we found that MRIA9, a newly developed small-molecule inhibitor of the salt-inducible-kinase 2, interferes with the cell division of cancer cells. More importantly, MRIA9 increases paclitaxel efficiency in eliminating ovarian cancer cells and patient derived cancer cells by inducing apoptosis or programmed cell death. Thus, our study indicates that MRIA9 might represent a novel therapeutical tool for translational studies to overcome paclitaxel resistance in ovarian cancer.The activity of the Salt inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK)-related kinase family, has been linked to several biological processes that maintain cellular and energetic homeostasis. SIK2 is overexpressed in several cancers, including ovarian cancer, where it promotes the proliferation of metastases. Furthermore, as a centrosome kinase, SIK2 has been shown to regulate the G2/M transition, and its depletion sensitizes ovarian cancer to paclitaxel-based chemotherapy. Here, we report the consequences of SIK2 inhibition on mitosis and synergies with paclitaxel in ovarian cancer using a novel and selective inhibitor, MRIA9. We show that MRIA9-induced inhibition of SIK2 blocks the centrosome disjunction, impairs the centrosome alignment, and causes spindle mispositioning during mitosis. Furthermore, the inhibition of SIK2 using MRIA9 increases chromosomal instability, revealing the role of SIK2 in maintaining genomic stability. Finally, MRIA9 treatment enhances the sensitivity to paclitaxel in 3D-spheroids derived from ovarian cancer cell lines and ovarian cancer patients. Our study suggests selective targeting of SIK2 in ovarian cancer as a therapeutic strategy for overcoming paclitaxel resistance.