4.6 Article

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

Journal

CANCERS
Volume 13, Issue 15, Pages -

Publisher

MDPI
DOI: 10.3390/cancers13153658

Keywords

Salt inducible kinase 2 (SIK2); the small molecule inhibitor MRIA9; spindle mispositioning; chromosomal instability; ovarian cancer; paclitaxel sensitization

Categories

Funding

  1. Deutsche Forschungsgemeinschaft [397659447]
  2. Deutsche Krebshilfe
  3. German Cancer Consortium (DKTK)
  4. Heidelberg and Verein zur Forderung der Wissenschaft
  5. Pravention and Therapie von Kehlkopfkrebs e.V.
  6. SGC, a registered charity [1097737]
  7. AbbVie
  8. Bayer AG
  9. Boehringer Ingelheim
  10. Canada Foundation for Innovation
  11. Eshelman Institute for Innovation
  12. Genentech
  13. Genome Canada through Ontario Genomics Institute [OGI-196]
  14. EU/EFPIA/OICR/McGill/KTH/Diamond
  15. Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN] [875510]
  16. Janssen
  17. Merck KGaA
  18. Merck Co.
  19. Pfizer
  20. SAo Paulo Research Foundation-FAPESP
  21. Takeda

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The study found that MRIA9 enhances the efficacy of paclitaxel in eliminating ovarian cancer cells and inhibits the activity of SIK2, leading to abnormal mitosis. Additionally, MRIA9 increases sensitivity to paclitaxel, suggesting selective targeting of SIK2 in ovarian cancer as a potential therapeutic strategy for overcoming paclitaxel resistance.
Simple Summary The 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.

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