Inactivation of BRCA2 in human cancer cells identifies a subset of tumors with enhanced sensitivity towards death receptormediated apoptosis
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Enrico N. De Toni1, Andreas Ziesch1, Antonia Rizzani1, Helga-Paula Török1, Sandra Hocke1, Shuai Lü1, Shao-Chun Wang2, Tomas Hucl3, Burkhard Göke1, Christiane Bruns4, Eike Gallmeier1,5
1Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany
2Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45267, USA
3Department of Gastroenterology and Hepatology, University of Prague, 14021 Prague 4, Czech Republic
4Department of Surgery, University of Magdeburg, 39120 Magdeburg, Germany
5Department of Gastroenterology, Philipps University Marburg, 35043 Marburg, Germany
Eike Gallmeier, e-mail: firstname.lastname@example.org
Enrico N. De Toni, e-mail: email@example.com
Keywords: apoptosis, BRCA2, gene targeting, targeted therapy, TRAIL
Received: July 26, 2015 Accepted: January 01, 2016 Published: January 28, 2016
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.
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