LOSS OF ATR SENSITIZES PANCREATIC CANCER CELLS TO REPLICATION STRESS

Candidate: Essam Karam
Supervisor: Dr. Sarah Sabatinos

ABSTRACT

ATR activity in the replication stability response enables cells to withstand the harmful effects of replication stress; a mechanism commonly utilized in chemotherapy. Targeting components of this pathway has shown to enhance sensitivity of cancer cells to replication stress, however the mechanism through sensitization remains unclear. We assessed the effects of ATR inhibition in pancreatic cancer cells under induced replication stress. We showed that ATR inhibition synergistically increased the cell death and antiproliferative effects of gemcitabine. Additionally, loss of ATR was found to alter cell size, chromosome missegregation and the cell cycle. From our results we can infer that loss of DNA repair through ATR inhibition prevents cells from regulating replication stress. This contributes to genomic instability that ultimately leads to apoptotic cell death. Our work aids in understanding how ATR inhibition contributes to susceptibility to replication stress; facilitating the advancement of targeted therapies.