Exploration of SIK2-signaling in ovarian cancer with CCNE1-amplification3

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Despite a high overall initial response to standard chemotherapy, the majority of epithelial ovarian cancer (EOC) patients die from the progressive growth of recurrent chemotherapy-resistant disease. The most significant advance in the chemotherapy was the introduction of paclitaxel to the treatment of EOC patients. The toxicity profile favoring the carboplatin/paclitaxel regimen has now established this as standard of care in the first-line setting. However, it appears that a therapeutic ceiling with these drugs has been reached. Recent evidence make a compelling case for targeting salt-inducible kinase 2 (SIK2) for therapy in ovarian cancer. SIK2 is over-expressed in omental metastases compared with primary tissues. Overexpression of SIK2 promotes abdominal metastasis in vivo. Although the established function of SIK2 is in the regulation of cellular metabolism, it’s role for the progression of ovarian cancer cells with CCNE1-amplification (30% of all ovarian cancers) through mitosis remains elusive. In this project, we plan to establish a structural model of the SIK2 catalytic domain, which is a prerequisite for an improved understanding for the regulation of the SIK2 catalytic activity and for the rational design of inhibitors. The detailed analysis of the role of SIK2 in the development of ovarian cancer with CCNE1-amplification in vitro and in vivo requires the use of specific SIK2 inhibitors. To further our understanding of SIK2 signaling in different stages of the cell cycle including mitosis, we plan to analyze the interactome and the phosphorylation of SIK2 in conjunction with the crystal structure of SIK2. Novel interacting partners will be functionally characterized. Importantly, we will also test novel inhibitors for targeted and combinatorial therapies (taxane/carboplatin) of ovarian cancer cells with CCNE1-amplification. Small molecules targeting SIK2 will have the potential to block two major pathways involved in metabolic regulation and the crosstalk between cancer cells and the microenvironment that both contribute to the establishment and growth of tumor metastasis.