Novel prognostic biomarkers and therapeutic targets for non-small cell lung cancer: Unravelling the role of Polo-like kinase 1
26 February 2018
UAntwerp - Campus Drie Eiken - Building Q - Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (route: UAntwerpen, Campus Drie Eiken
Jolien Van den Bossche
Prof A. Wouters, Prof F. Lardon, Prof M. Peeters
PhD defence Jolien Van den Bossche - Faculty of Medicine and Health Sciences
In recent years, 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 mitosis is a validated approach, and agents that affect the mitotic spindle are well-established components of many onco-therapeutic regimens. Nevertheless, serious adverse effects remain the dose-limiting factor. New approaches to mitosis inhibition rather target cardinal regulatory proteins and have the potential to overcome the limitations of traditional anti-mitotic agents. In this doctoral thesis, we focused on Polo-like kinase 1 (Plk1), one of most promising targets in this research field.
In the first part, we determined the clinicopathological significance of Plk1 mRNA and protein expression in combination with the TP53 mutation status, induction of apoptotic cell death and hypoxia in 98 NSCLC adenocarcinoma patients. We observed that Plk1 mRNA and protein expression and CA IX protein levels were upregulated in the majority of tumor samples, with the highest Plk1 mRNA and protein levels in TP53 mutated samples. Our results revealed that the outcome of patients with both Plk1 mRNA and CA IX overexpression, who also harbored a TP53 mutation, was significantly worse than that of patients with aberrant expression of only one of the three markers.
In the second part, we evaluated the in vitro therapeutic potential of the Plk1 inhibitor volasertib, in a panel of NSCLC cell lines with a different p53 background under both normal and reduced oxygen conditions. We revealed that volasertib monotherapy resulted in significantly more G2/M phase arrest in cells with non-functional p53, whereas in p53 wild type cells, predominantly cell death and cellular senescence were induced. Overall, the therapeutic effect of volasertib monotherapy was reduced under hypoxia. Interestingly, pre-treatment with the Plk1 inhibitor efficiently sensitized p53 wild type cells to irradiation. Flow cytometric analysis revealed that significantly more cells were arrested in mitosis after the combination therapy, however, no difference in the induction of apoptotic cell death could be observed. In addition, we noticed that after combining volasertib with irradiation, cellular senescence was mainly induced in cells with functional p53. While most cells with wild type p53 showed permanent growth arrest, more p53 knockdown/mutant cells could re-enter the cell cycle, resulting in colony formation and cell survival.
In conclusion, we can state that although further validation in animal models and patients is required, our preclinical results may have an important impact on the clinical use of Plk1 inhibitors in NSCLC patients.