Replication fork collapse through ATR inhibition as a cancer treatment
Dr Eric Brown, University of Pennsylvania
Date & Time:
Friday, 24 July 2015, 12:15
Dr. Brown studies the mechanisms that safeguard genome integrity during replication and investigates how defects in these processes impact tissue homoeostasis, cancer risk, and cancer treatment. His work has focused on three specific areas: 1) cell extrinsic mechanisms that limit the accumulation replication stress-induced DNA damage in tissues[1,2], 2) the promise of ATR-CHK1 pathway inhibitors as cancer treatments[1-4], and 3) the role of ATR in preventing replication fork collapse and genomic instability[5,6]. In regards to the third research area, Dr. Brown’s laboratory has studied on how layered networks of checkpoint and repair genes cooperate to suppress double strand breaks in S phase and has identified novel synthetic lethal interactions for potential use in cancer treatment. His laboratory’s most recent study in this area implicates the AURKA-PLK1 pathway and the SUMO-targeted Ubiquitin ligase RNF4 as driving forces in replication fork collapse when ATR function is compromised. This work and Dr. Brown’s demonstration that ATR-CHK1 inhibition is synthetically lethal with oncogene expression[3,4] have remarkable potential for clinical application, particularly in terms of the breadth of cancers in which ATR and CHK1 inhibitors may be applied.