Sensitization of cancers to ATR inhibition via elevated Aurora A-PLK1 activity

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

DESCRIPTION (provided by applicant): We and others have shown that common genetic alterations in cancer (KrasG12D, HrasG12V, Myc-C overexpression, and p53 deficiency) lead to an increased reliance on ATR for genome maintenance and cell viability. In addition, we have recently demonstrated that the Aurora-Plk1 pathway strongly promotes DNA replication failure in ATR suppressed cells. We propose that these interactions the ATR pathway may generate a therapeutic window in which ATR suppression can be used to treat fully-developed malignancies. Through a novel cell culture system for detection of replication recovery, we will 1) determine the mechanism by which replication forks restart in an ATR-depleted environment, and 2) investigate if cells over expressing components of the PLK1 pathway are hypersensitive to loss of ATR. Furthermore, the information gained from this work will then be used in culture and transplantation modl systems to examine the biological effects of ATR suppression in cell lines and tumors expressing components of the PLK1 pathway. Finally we will explore the potential therapeutic benefit of ATR suppression in an in vivo model system of colon tumorigenesis (APCmin/+), which through stimulation of the c-Myc transcriptional pathway exhibits upregulated Aurora-Plk1 activity. In aggregate, these studies will determine if Aurora-Plk1 over stimulation provides and optimal genetic context for ATR suppression in cancer therapy and explore the mechanisms by which ATR suppression preferentially limits the progression of these cancers.