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[초청강연] Redefining therapy response in BRCA cancer

2019-11-05l Hit 1996

Date: 2019-11-15 16:00 ~ 17:00
Speaker: Prof. Sharon Cantor (University of Massachusetts Medical School)
Professor: Prof. Hyunsook Lee
Location: Bldg 500, Mok-Am Hall
Abstract:
BRCA1 or BRCA2 (BRCA)-deficient tumor cells have defects in DNA repair by homologous recombination and DNA replication fork stability that is thought to underlie poly(ADP) ribose polymerase, PARP inhibitor (PARPi) sensitivity. However, new findings indicate that PARPi do not initially generate DNA breaks or pause replication forks, but rather accelerate DNA replication forks. Thus, we tested the hypothesis that sensitivity results from combined replication dysfunction. Consistent with this interpretation, here we demonstrate that PARPi-induced replication acceleration is exacerbated in BRCA deficient cells, but avoided in cells that are not sensitive to PARPi. Furthermore, in BRCA deficient -tissue culture and -patient tumors and in known and de novo models of PARPi resistance, we find that this replication dysfunction is suppressed. Collectively a molecular link between PARPi sensitivity and replication dysfunction provides a new paradigm for understanding synthetic lethal interactions in BRCA cancer.