Defining BRCA replication dysfunction in therapy response

The goal of this grant is to harness a new understanding of vulnerabilities in tumors with mutations in the
hereditary breast cancer genes. We have found that cells deficient in the BRCA-pathway genes, fail to properly
respond to DNA replication perturbations (stress) and consequently replication is not restrained properly and
ssDNA regions (gaps) develop. We find that when gaps are present, BRCA cancer cells are sensitive to therapy
and when gaps are avoided, resistance occurs. Our findings that gaps are fundamental to therapy response is
a paradigm shift in the current framework that proposes that persistent DNA breaks and fork degradation is the
cause of sensitivity. Thus, we propose to employ state-of-the-art experiments to map the molecular determinants
of this BRCA pathway fork restraint function. Moreover, will identify the gap making machinery that is critical for
therapy response and the gap avoidance machinery that is critical to therapy resistance. Lastly, we will re-
examine models of therapy resistance previously attributed to restored DNA repair and fork protection and
determine if gap suppression is instead the fundamental resistance mechanism. Collectively, these proposed
studies will identify how cancer cells succumb to and eventually gain resistance to chemotherapy and provide
valuable insight towards biomarkers predicting resistance and drugs that prevent resistance.

Grant Number: 5R01CA254037-05
NIH Institute/Center: NIH
Principal Investigator: Sharon Cantor