Determining how PRP4K insufficiency impacts cancer signaling and therapy responses

The pre-mRNA processing factor kinase PRP4K is a gene that is highly conserved and found in many organisms from single cell organisms to humans. Although PRP4K is an essential gene due to its role in regulating the splicing of the messenger RNA molecules that instruct the cell to make different proteins, partial loss of PRP4K gene and protein expression is found in breast and ovarian cancers. Dr. Graham Dellaire, who identified the mouse and human genes for PRP4K, has been studying PRP4K for over 20 years. Despite being an essential protein in human cells, work from the Dellaire laboratory and others has demonstrated that partial loss of PRP4K expression leads to messenger RNA and cellular changes that make breast and ovarian cancers more aggressive and less sensitive to taxanes, a class of chemotherapy drugs known that target rapidly growing cells. How loss of PRP4K makes cancer more aggressive is only partially understood, and it is unknown how PRP4K-low cancers respond to other forms of chemotherapy. When tumours grow, they are subjected to oxidative cell stresses that cause them to activate detoxifying anti-oxidant signaling pathways. These pathways control gene expression programs that affect chemotherapy responses and cancer cell survival. In this study, we will determine how PRP4K loss alters cancer cell signaling in response to these stresses and impacts therapy responses. Ultimately, this study will provide new knowledge that could improve patient outcomes by contributing to new cancer therapeutic approaches and more effective application of existing chemotherapy to treat patients with tumours expressing low levels of PRP4K.