Abstract
Important advances have been made in our understanding of the molecular pathways governing cell function in cancer. This has led to an explosive interest in molecular targeted agents. Targeting mitotic cell division is a validated approach to inhibit tumor growth and agents that affect the mitotic spindle are well-established components of many oncotherapeutic regimes. One such mitotic cancer target is Polo-like kinase 1 (Plk1), a key regulator of multiple steps during mitosis. Several studies have demonstrated overexpression of Plk1 in a number of human malignancies, indicating a therapeutic potential for Plk1 inhibitors in a range of solid tumor types.
Previously, we investigated volasertib, currently considered as the most promising Plk1 inhibitor, in a series of non-small cell lung carcinoma (NSCLC) cell lines with different P53 status. Volasertib established a dose-dependent growth inhibition in all cell lines tested. Interestingly, apoptotic cell death was induced in P53 wild type cells, while P53 deficient cells arrested in the G2/M phase of the cell cycle upon Plk1 inhibition.
In the current research project, the relationship between Plk1 and P53 will be further investigated in order to increase the therapeutic efficacy of volasertib, possibly by using P53 as a predictive biomarker. Therefore, the effect of Plk1 inhibition on the mitotic spindle and several P53 targets will be tested.
Furthermore, our experiments demonstrated that Plk1 inhibition can induce senescence, a terminal growth arrest resulting from serious DNA damage or cellular stress. Hence, the correlation between cellular stress, the TP53 status of cancer cells and the induction of senescence will be examined.
To end with, most cancer treatments are combinations of chemotherapeutic agents and/or radiotherapy, and it is expected that Plk1 inhibitors will acheive their greatest efficacy in combination with conventional treatments. Preliminary data showed a strong radiosensitising effect of volasertib in A549 NSCLC cells. In the final part of this research project, the molecular pathways underlying the observed radiosensitizing effect will be investigated, focussing also on the P53 status of cancer cells.
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