Glioblastoma Cells Containing Mutations in the Cohesin Component STAG2 Are Sensitive to PARP Inhibition
Glioblastoma Cells Containing Mutations in the Cohesin Component STAG2 Are Sensitive to PARP Inhibition
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DOI：
10.1158/1535-7163.mct-13-0749
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发表时间：
2014-03-01
影响因子：
5.7
通讯作者：
Hieter, Philip
中科院分区：
文献类型：
--
作者：
Bailey, Melanie L.;O'Neil, Nigel J.;Hieter, Philip
最近的数据已经确定了STAG2，多功能粘附素复合物的核心亚基，作为几种类型的癌症中的高度复发性突变基因。我们试图确定一种治疗策略，以选择性地靶向癌细胞窝藏失活突变的STAG2使用两个独立的对的同基因胶质母细胞瘤细胞系含有内源性突变STAG2等位基因或野生型STAG2等位基因恢复同源重组。我们发现STAG2的突变与DNA修复酶PARP抑制剂的敏感性显著增加有关。与野生型STAG 2细胞相比，STAG 2突变的PARP抑制细胞在G（2）期累积，并且具有更高百分比的微核、碎裂的核和染色质桥。我们还观察到STAG2突变的胶质母细胞瘤细胞中有更多的53BP1病灶，这表明这些细胞在DNA修复方面存在缺陷。此外，当PARP抑制剂与DNA损伤剂联合使用时，STAG2突变的细胞比野生型STAG2的细胞更敏感。这些数据表明，PARP是STAG 2中含有失活突变的肿瘤的潜在靶点，并强烈建议在临床试验中确定STAG 2状态并将其与PARP抑制剂的治疗反应相关，无论是前瞻性还是回顾性。（C）2013年AACR。
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 G(2) 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. (C)2013 AACR.