title: Glioblastoma cells containing mutations in the cohesin component STAG2 are sensitive to PARP inhibition.
abstract: Recent data have identified STAG2, a core subunit of the multifunctional cohesin complex, as a highly recurrently mutated gene in several types of cancer. We sought to identify a therapeutic strategy to selectively target cancer cells harboring inactivating mutations of STAG2 using two independent pairs of isogenic glioblastoma cell lines containing either an endogenous mutant STAG2 allele or a wild-type STAG2 allele restored by homologous recombination. We find that mutations in STAG2 are associated with significantly increased sensitivity to inhibitors of the DNA repair enzyme PARP. STAG2-mutated, PARP-inhibited cells accumulated in G2 phase and had a higher percentage of micronuclei, fragmented nuclei, and chromatin bridges compared with wild-type STAG2 cells. We also observed more 53BP1 foci in STAG2-mutated glioblastoma cells, suggesting that these cells have defects in DNA repair. Furthermore, cells with mutations in STAG2 were more sensitive than cells with wild-type STAG2 when PARP inhibitors were used in combination with DNA-damaging agents. These data suggest that PARP is a potential target for tumors harboring inactivating mutations in STAG2, and strongly recommend that STAG2 status be determined and correlated with therapeutic response to PARP inhibitors, both prospectively and retrospectively, in clinical trials.
authors.affiliation: Corresponding Author: Philip Hieter, Michael Smith Laboratories, 2185 East Mall, Room 323, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z4. hieter@msl.ubc.ca.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Bailey
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: O'Neil
authors.forename: Derek M
authors.initials: DM
authors.lastname: van Pel
authors.forename: David A
authors.initials: DA
authors.lastname: Solomon
authors.forename: Todd
authors.initials: T
authors.lastname: Waldman
authors.forename: Philip
authors.initials: P
authors.lastname: Hieter
mesh_terms: D034961:Antigens, Nuclear / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009154:Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics*; D000097722:Cohesins
chemical_list: D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004791:Enzyme Inhibitors; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D000097722:Cohesins; C508565:STAG2 protein, human; C499320:PARP1 protein, human