The Replication Stress Response in Pancreatic Cancer
Final rept. 30 Sep 2012-29 Sep 2014
EMORY UNIV ATLANTA GA SCHOOL OF MEDICINE
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Pancreatic cancer is a highly lethal malignancy with an expected 5-year survival of less than 5 for all patients using current therapies. Most of these therapies rely on inducing DNA damage and replication blocks to cause cell death however the effectiveness of these treatments is often limited to a subset of patients that respond to treatment. Understanding why patients are sensitive or resistant to specific treatments would allow the personalization of therapies that are most effective for a patient while potentially reducing toxicity. The Replication Stress Response RSR is a signaling network that recognizes challenges to DNA replication and mobilizes diverse activities to maintain genome integrity. The RSR is critical for the prevention of pancreatic cancer by acting as a barrier against genomic instability and tumorigenesis. We hypothesized that novel RSR genes maintain genome integrity by participating in an ATR-mediated replication stress response and that dysregulation of RSR genes and their cancer barrier function results in the development of pancreatic cancer. Utilizing a custom generated siRNA library targeting genes somatically mutated in pancreatic cancer from the Sanger COSMIC library, we completed a synthetic lethal screen to identify genes which when silenced mediate gemcitabine sensitivity in human pancreatic cancer cells. We further validated positive hits be deconvolution of individual siRNAs and characterized their activities in DNA replication and the DNA damage response. We determined whether these genes were dysregulated and differentially expressed in pancreatic cancer cell lines and patient samples using published data sets.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research