title: Inactivation of BRCA2 in human cancer cells identifies a subset of tumors with enhanced sensitivity towards death receptor-mediated apoptosis.
abstract: OBJECTIVE
  DNA repair defects due to detrimental BRCA2-mutations confer increased susceptibility towards DNA interstrand-crosslinking (ICL) agents and define patient subpopulations for individualized genotype-based cancer therapy. However, due to the side effects of these drugs, there is a need to identify additional agents, which could be used alone or in combination with ICL-agents. Therefore, we investigated whether BRCA2-mutations might also increase the sensitivity towards TRAIL-receptors (TRAIL-R)-targeting compounds.
  
  
  METHODS
  Two independent model systems were applied: a BRCA2 gene knockout and a BRCA2 gene complementation model. The effects of TRAIL-R-targeting compounds and ICL-agents on cell viability, apoptosis and cell cycle distribution were compared in BRCA2-proficient versus-deficient cancer cells in vitro. In addition, the effects of the TRAIL-R2-targeting antibody LBY135 were assessed in vivo using a murine tumor xenograft model.
  
  
  RESULTS
  BRCA2-deficient cancer cells displayed an increased sensitivity towards TRAIL-R-targeting agents. These effects exceeded and were mechanistically distinguishable from the well-established effects of ICL-agents. In vitro, ICL-agents expectedly induced an early cell cycle arrest followed by delayed apoptosis, whereas TRAIL-R-targeting compounds caused early apoptosis without prior cell cycle arrest. In vivo, treatment with LBY135 significantly reduced the tumor growth of BRCA2-deficient cancer cells in a xenograft model.
  
  
  CONCLUSIONS
  BRCA2 mutations strongly increase the in vitro- and in vivo-sensitivity of cancer cells towards TRAIL-R-mediated apoptosis. This effect is mechanistically distinguishable from the well-established ICL-hypersensitivity of BRCA2-deficient cells. Our study thus defines a new genetic subpopulation of cancers susceptible towards TRAIL-R-targeting compounds, which could facilitate novel therapeutic approaches for patients with BRCA2-deficient tumors.
authors: Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors: Enrico N
authors: EN
authors: De Toni
authors: Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors: Andreas
authors: A
authors: Ziesch
authors: Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors: Antonia
authors: A
authors: Rizzani
authors: Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors: Helga-Paula
authors: HP
authors: Török
authors: Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors: Sandra
authors: S
authors: Hocke
authors: Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors: Shuai
authors: S
authors: Lü
authors: Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors: Shao-Chun
authors: SC
authors: Wang
authors: Department of Gastroenterology and Hepatology, University of Prague, 14021 Prague 4, Czech Republic.
authors: Tomas
authors: T
authors: Hucl
authors: Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
authors: Burkhard
authors: B
authors: Göke
authors: Department of Surgery, University of Magdeburg, 39120 Magdeburg, Germany.
authors: Christiane
authors: C
authors: Bruns
authors: Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.|Department of Gastroenterology, Philipps University Marburg, 35043 Marburg, Germany.
authors: Eike
authors: E
authors: Gallmeier
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D024682:BRCA2 Protein / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004260:DNA Repair / Q000235:genetics; D006801:Humans; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors*
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D003432:Cross-Linking Reagents; C000592141:LBY135 monoclonal antibody; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human
keywords: BRCA2; TRAIL; apoptosis; gene targeting; targeted therapy