Matthew Wakefield, PhD
The Walter & Eliza Hall Institute of Medical Research
2020 Rosser Family Pilot Study Award
Identifying all mutations in the PARP1 catalytic domain that impact PARP inhibitor action
PARP inhibitors are a class of drugs that are becoming a major part of treatment for high grade ovarian cancer. These drugs kill cancer cells by targeting a protein called PARP1. Though PARP inhibitors are effective at killing the majority of cancer cells, a small number of cancer cells can survive treatment if they have genetic mutations that cause resistance. One type of mutations that occur are changes to the PARP1 protein itself, such that it can no longer be inhibited by the drugs. In this study, Dr. Wakefield will use a technology called Deep Mutational Sequencing to create all of the thousands of possible mutations that could occur in the PARP1 protein. He will then systematically test which of those mutations affect how cancer cells respond to treatment with PARP inhibitors. This study will provide basic knowledge about how PARP1 interacts with existing inhibitors, which will assist in the design of more effective PARP inhibitors. By providing a better understanding of PARP1 mutations, this will ultimately allow clinicians to select the best drug for treatment based on a patient’s PARP1 mutations.