Inactivation ofBRCA2in human cancer cells identifies a subset of tumors with enhanced sensitivity towards death receptormediated apoptosis

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// Enrico N. De Toni 1 , Andreas Ziesch 1 , Antonia Rizzani 1 , Helga-Paula Török 1 , Sandra Hocke 1 , Shuai Lü 1 , Shao-Chun Wang 2 , Tomas Hucl 3 , Burkhard Göke 1 , Christiane Bruns 4 , Eike Gallmeier 1, 5 1 Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany 2 Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45267, USA 3 Department of Gastroenterology and Hepatology, University of Prague, 14021 Prague 4, Czech Republic 4 Department of Surgery, University of Magdeburg, 39120 Magdeburg, Germany 5 Department of Gastroenterology, Philipps University Marburg, 35043 Marburg, Germany Correspondence to: Eike Gallmeier, e-mail: eike.gallmeier@med.uni-marburg.de Enrico N. De Toni, e-mail: enrico.detoni@med.uni-muenchen.de Keywords: apoptosis, BRCA2, gene targeting, targeted therapy, TRAIL Received: July 26, 2015 Accepted: January 01, 2016 Published: January 28, 2016 ABSTRACT Purpose: 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. Experimental design: 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.