There is a delicate and synchronized balance that allows a cell to select the appropriate DNA repair pathway for each DNA lesion that it encounters. This balance is pivotal because erroneous or dysregulated DNA repair can result in mutations and chromosomal aberrations, which are known to drive genomic instability. Cancers driven by defects in DNA repair pathways were once thought to be limited to rare inherited mutations in a few DNA repair proteins, but data generated by the Cancer Genome Atlas shows that the vast majority of cancers are genomically unstable and thus likely have acquired a DNA repair defect.
Our research aims to identify novel mutations in DNA repair proteins in breast, pancreatic, and head and neck cancers that drive aberrant DNA repair and signaling, resulting in carcinogenesis. The goal is to clearly define how these mutations affect specific DNA repair pathways in order to identify agents or combined modality therapies with radiation treatment that selectively kill cancers with these mutations. Furthermore, cancers with a loss in a DNA repair component typically become addicted to another repair pathway(s) to survive and proliferate. This addiction can be exploited therapeutically by inhibiting the DNA repair pathway the cancer cell has become addicted to. We use a combination of genomics, proteomics, biochemistry, cell biology, microscopy, and tumorigenic mouse models to understand how aberrant DSB repair and signaling results in tumorigenesis and how these defects can be exploited therapeutically.