Implication of DYRK1B kinase in dormant glioblastoma cancers and utilization of DYRK1B inhibitors as a novel therapeutic strategy for glioblastoma.

Abstract

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.

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“…It has been shown that proteins involved in main cell metabolic processes can be altered in diseases such as cancer, especially in those involved in processes that promote proliferation and survival. The presence of DYRK1B in glioblastoma, which has been characterized for this specific type of cancer (Vilenchik et al, 2019), and which has been stably found in clinical samples, control β-actina, determinado por Western blot. c-d) Porcentaje de células positivas para ALDH1A1 y DYRK1B con respecto a su patrón de expresión observado.…”

Novel Efficient Multistage Lead Optimization Pipeline Experimentally Validated for DYRK1B Selective Inhibitors

“…DYRK1B is overexpressed in several cancer types and maintains cellular quiescence . Moreover, DYRK1B can enhance cancer cell survival by upregulating antioxidant gene expression and reducing intracellular levels of reactive oxygen species. , It is well documented that either genetic depletion of DYRK1B or its pharmacological inhibition leads to the cell cycle re-entry and apoptosis of DYRK1B-expressing quiescent cancer cells, − which brings DYRK1B inhibitors in focus of novel highly potent cancer therapies. At the same time, the inhibition of the DYRK1A kinase, which has high homology to DYRK1B in its active site yet different functions and tissue distribution, bears risks of adverse drug reactions because DYRK1A is expressed in multiple tissues and is involved in a plethora of housekeeping cellular processes .…”