PLK1 in OSCC: Basic Biology and Novel Therapeutic Approaches

Oral squamous cell carcinoma (OSCC) is the most frequent tumor type of the oral cavity and associated with substantial morbidity and a poor prognosis. Excessive consumption of alcohol and tobacco products are the main risk factors. Therapeutic options include surgery, radiation, and chemotherapy. More recently, these have been complemented by the targeted drug Cetuximab and immunotherapy, both of which, however, are less effective in OSCC than in other tumor types. Modern cancer research aims at understanding the biological and molecular mechanisms of tumorigenesis, with the goal to develop drugs targeting them in a specific manner. Indeed, a substantial number of such targeted drugs has alredy entered clinical routine. They are more specific for cancer vs. normal cells than chemotherapy, and thus usually associated with fewer side effects. Several biological mechanisms can lead to therapeutically approachable differences between cancer and normal cells. Among them is increased expression (and consequently, increased activity) of cancer driver genes (i.e., oncogenes). In preparatory work, we have used publicly available gene expression data sets to search for genes whose expression is consistently altered in OSCC compared to normal oral mucosa. Through application of stringent filter criteria to the resulting gene list, we identified Polo-like kinase 1 (PLK1) as an interesting candidate for targeted therapy of OSCC. PLK1 has been described as an oncogene in other tumor types, and to some extent also in OSCC. This has led to the development of PLK1 inhibitors, which, however, have not yet been approved for the treatment of OSCC. The current project will address understudied aspects of the biological function of PLK1 in OSCC including its impact on chromosomal instability, a property allowing tumors to adapt to alterated environments and fostering the development of therapy resistance. Moreover, alternative approaches towards the therapeutic exploitation of PLK1 overexpression in OSCC shall be explored: substances acting synergistically with PLK1 inhibitors, as well as drugs with particularly high activity in PLK1 overexpressing cells, shall be identified through a combination of genetic and pharmacological experiments. The project will be executed in an international collaboration with the groups of Matouš Hrdinka, Ostrava, CZ, and Marcela Buchtov, Brno, CZ. Its results will enhance our understanding of the biological roles of PLK1 in OSCC and highlight novel approaches towards therapeutic exploitation of this oncogene.