title: Synthetic lethality of PARP inhibition in BRCA-network disrupted tumor cells is associated with interferon pathway activation and enhanced by interferon-γ.
abstract: Tumor suppressor genes BRCA1 and BRCA2 function in a complex gene network that regulates homologous recombination and DNA double-strand break repair. Disruption of the BRCA-network through gene mutation, deletion, or RNAi-mediated silencing can sensitize cells to small molecule inhibitors of poly (ADP-ribose) polymerase (PARPi). Here, we demonstrate that BRCA-network disruption in the presence of PARPi leads to the selective induction and enhancement of interferon pathway and apoptotic gene expression in cultured tumor cells. In addition, we report PARPi cytotoxicity in BRCA1-deficient tumor cells is enhanced >10-fold when combined with interferon-γ. These findings establish a link between synthetic lethality of PARPi in BRCA-network disrupted cells and interferon pathway activation triggered by genetic instability.
authors.affiliation: Rosetta Inpharmatics LLC, A Wholly Owned Subsidiary of Merck & Co., Inc, Seattle, WA 98109, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Warrener
authors.forename: Sammy
authors.initials: S
authors.lastname: Kim
authors.forename: Sybil M G
authors.initials: SM
authors.lastname: Williams
authors.forename: Matthew
authors.initials: M
authors.lastname: Biery
authors.forename: Marcia
authors.initials: M
authors.lastname: Gordon
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.forename: Michele A
authors.initials: MA
authors.lastname: Cleary
authors.forename: Peter S
authors.initials: PS
authors.lastname: Linsley
authors.forename: Michael
authors.initials: M
authors.lastname: Carleton
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics*; D020868:Gene Silencing / Q000187:drug effects; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C484606:SEM1 protein, human; D007371:Interferon-gamma; D011065:Poly(ADP-ribose) Polymerases; D046988:Proteasome Endopeptidase Complex