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.