De Toni Enrico N, Ziesch Andreas, Rizzani Antonia, Török Helga-Paula, Hocke Sandra, Lü Shuai, Wang Shao-Chun, Hucl Tomas, Göke Burkhard, Bruns Christiane, Gallmeier Eike
Department of Medicine II, Ludwig-Maximilians-University, 81377 Munich, Germany.
Department of Cancer Biology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
Oncotarget. 2016 Feb 23;7(8):9477-90. doi: 10.18632/oncotarget.7053.
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.
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.
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.
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.
有害的BRCA2突变导致的DNA修复缺陷会增加对DNA链间交联（ICL）剂的易感性，并为基于个体基因型的癌症治疗定义患者亚群。然而，由于这些药物的副作用，需要鉴定可单独使用或与ICL剂联合使用的其他药物。因此，我们研究了BRCA2突变是否也会增加对靶向TRAIL受体（TRAIL-R）的化合物的敏感性。
应用了两个独立的模型系统：BRCA2基因敲除模型和BRCA2基因互补模型。在体外，比较了靶向TRAIL-R的化合物和ICL剂对BRCA2功能正常与缺陷的癌细胞的细胞活力、凋亡和细胞周期分布的影响。此外，使用小鼠肿瘤异种移植模型在体内评估了靶向TRAIL-R2的抗体LBY135的作用。
BRCA2缺陷的癌细胞对靶向TRAIL-R的药物表现出更高的敏感性。这些作用超过了ICL剂已明确的作用，并且在机制上可与之区分。在体外，ICL剂预期会诱导早期细胞周期停滞，随后延迟凋亡，而靶向TRAIL-R的化合物会导致早期凋亡，而无先前的细胞周期停滞。在体内，用LBY135治疗在异种移植模型中显著降低了BRCA2缺陷癌细胞的肿瘤生长。
BRCA2突变显著增加癌细胞在体外和体内对TRAIL-R介导的凋亡的敏感性。这种作用在机制上可与BRCA2缺陷细胞已明确的ICL超敏反应区分开来。因此，我们的研究定义了一类对靶向TRAIL-R的化合物敏感的新的癌症遗传亚群，这可能有助于为BRCA2缺陷肿瘤患者开发新的治疗方法。
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