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Majority of tumors consist of two populations of cancer cells: actively proliferating and those in the reversible dormant or quiescent state, which contribute to the resistance of human tumors to chemotherapies. Conventional chemotherapeutic agents have limited efficacy in ovarian adenocarcinoma patients: while the appropriate chemotherapeutic agent kills proliferating cancer cells, dormant cancer cells survive the treatments and result in recurrent disease. The presence of dormant cancer cells is not revealed by standard H&E staining and morphological tumor analysis. CDK inhibitor p27 is known to be a marker of the dormant state. DYRK1B kinase (serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B) is associated with survival of many types of cancers and was shown to play a key role in maintaining the cancer cells in quiescent state by stabilizing p27 and by inducing the breakdown of cyclin D isoforms. In this study, we investigated the functional and therapeutic relevance of DYRK1B in ovarian carcinomas. We have conducted an immunohistochemical study of 70 human ovarian tumors (35 primary/treatment-naive and 35 recurrent/standard chemotherapy resistant ones) and 20+ cases of normal and benign ovarian tissues for expression of DYRK1B, p27 and Ki-67. All FFPE tissue samples have been obtained from the consented patients and under the IRB-approved protocols clinical network, groups have been normalized for age and the disease type/stage. High levels of DYRK1B and p27 proteins expression in malignant treatment-naïve tumors and their significant correlation indicates the presence of dormant cancer cells mixed up with the proliferating ones within patient’s tumors. This effect was detected regardless of the tumor histological subtype (endometrial, serous, mucinous, etc.) and/or stage. While all advanced stage tumors (Stage IIIC and IV) overexpress both markers of dormancy; the early stage tumors (Stage I-II) also presented a higher number of cases with greatly positive scores. Tissue microarray and immunohistochemistry analysis in the literature showed that higher expression levels of DYRK1B correlated with a worse prognosis. We suggest that specific immunostaining of DYRK1B in tumor and endothelial cells can be explored as a predictive risk factor of time to progression/death in patients with primary ovarian tumors. Inhibition of DYRK1B kinase activity with FX9847, specific and selective DYRK1B inhibitor, inhibited ovarian cancer cell growth and induced apoptosis. Moreover, combination of FX9847 with chemotherapeutic agents such as taxanes or vinca alkaloids demonstrated an increased anti-cancer effect on ovarian cancer cells. Together, these findings suggest that DYRK1B is critically involved in the survival of ovarian carcinoma providing a new rationale for their treatment with the kinase inhibitors. Citation Format: Alexandra Kuznetsova, Arianna Damiani, Lita De Leon, Michael Frid, Menelik Duey, Jason Law, Olga Potapova, Maria Vilenchik. Implication of DYRK1B Kinase in ovarian cancers and utilization of DYRK1B Inhibitors as a novel therapeutic strategy for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3038.

e14670 Background: A major determinant of cancer resistance and recurrence is the presence of quiescent cancer cells. It has long been known that quiescent cancers are resistant to a wide variety of anti-cancer therapeutics relative to actively proliferating cells. However, the presence and relative size of the quiescent compartment is not revealed by standard H&E staining and morphological tumor analysis and, therefore, the data demonstrating its importance and prevalence by tumor type are lacking. DYRK1B kinase (serine/threonine-protein kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1B) is associated with growth and survival of many types of cancer cells and was shown to play a key role in maintaining the cancer cells in reversible quiescent state by stabilizing the CDK inhibitor p27 and by inducing the breakdown of cyclin D isoforms. Methods: We conducted an immunohistochemical study of 80 human glioblastoma (GBM) tumors (primary / treatment-naive, Grade IV) and 10 cases of normal postmortem brain tissues for expression of DYRK1B, and quiescence and proliferation markers p27 and Ki-67, respectively. For subsection of these tissues, high levels of DYRK1B and p27 expression were observed. Results: In this study, we investigated the functional and therapeutic relevance of DYRK1B expression in glioblastomas, the most common brain cancer in adults. It is an aggressive, highly resistant to treatment tumor type with median survival time of less than 16 months following surgery and treatment. Conclusions: There was a statistically significant correlation between immunostaining of DYRK1B and p27, indicating the presence of dormant cancer cells mixed with the proliferating cancer cells within the patients' tumors. We suggest that DYRK1B inhibitors in combination with chemotherapeutics agents have a potential to improve patient treatment outcome and prolong survival.