南医大王慧博教授著名期刊揭示脑胶质瘤母细胞瘤耐药机制

近日南京医科大学的研究人员揭示脑胶质瘤母细胞瘤（GBM）替莫唑胺（TMZ）耐药新机制，该研究于2016年3月9日在线发表于美国癌症研究协会(American Association for Cancer Research，AACR)著名杂志Cancer Research（最新影响因子9.329）上，这项研究为逆转 TMZ 获得性耐药提供新的方法和思路。

　　

生物通报道：脑胶质母细胞瘤（GBM）获得性耐药是临床上的一个重要难题，大大限制其治疗效果，然而目前关于耐药性产生的具体机制还不甚清楚。

南京医科大学第一附属医院神经外科王慧博教授研究团队揭示了脑胶质瘤母细胞瘤（GBM）替莫唑胺（TMZ）耐药新机制，为克服TMZ耐药提供了潜在途径。这项研究于2016年3月9日在线发表于国际肿瘤学著名杂志Cancer Research（最新影响因子9.329）上。文章的通讯作者是南京医科大学神经外科的王慧博教授。

Pol κ 是一种参与跨损伤DNA合成的易误修复聚合酶，在该文章中，研究人员发现GBM细胞株及GBM患者原代细胞在TMZ治疗后会出现Pol κ显著上调，过表达Pol κ使那些原本对TMZ敏感的细胞产生抵抗。在体外实验和小鼠模型中抑制Pol κ，能让耐药的GBM细胞重新对TMZ敏感。

进一步的机制研究发现，去除Pol κ会破坏同源重组（HR）介导的修复，干扰停滞复制叉的重新启动，影响ATR-Chk1信号通路的激活，延迟细胞周期的进程。在去除Pol κ的耐药GBM细胞中过表达Rad17，可以恢复细胞的HR效率，帮助细胞清除TMZ诱导的DNA断裂，导致这些细胞产生耐药。

该研究成果揭示了跨损伤DNA合成通路在TMZ耐药中的重要作用，针对该通路的靶向治疗将可能成为逆转耐药的潜在手段，为提高GBM患者临床疗效提供重要的理论依据。

生物通推荐原文摘要：

The error-prone DNA polymerase κ promotes temozolomide resistance in glioblastoma through Rad17-dependent activation of ATR-Chk1 signaling

The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of human cancers, including glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that Pol κ, an error-prone polymerase that participates in translesion DNA synthesis, was significantly upregulated in GBM cell lines and tumor tissues following temozolomide (TMZ) treatment. Overexpression of Pol κ in TMZ-sensitive GBM cells conferred resistance to TMZ, whereas its inhibition markedly sensitized resistant cells to TMZ in vitro and in orthotopic xenograft mouse models. Mechanistically, depletion of Pol κ disrupted homologous recombination (HR)-mediated repair and restart of stalled replication forks, impaired the activation of ATR-Chk1 signaling, and delayed cell cycle re-entry and progression. Further investigation of the relationship between Pol κ and TMZ revealed that Pol κ inactivation facilitated TMZ-induced Rad17 ubiquitination and proteasomal degradation, subsequently silencing ATR-Chk1 signaling and leading to defective HR repair and the reversal of TMZ resistance. Moreover, overexpression of Rad17 in Pol κ-depleted GBM cells restored HR efficiency, promoted the clearance of TMZ-induced DNA breaks, and desensitized cells to the cytotoxic effects of TMZ observed in the absence of Pol κ. Finally, we found that Pol κ overexpression correlated with poor prognosis in GBM patients undergoing TMZ therapy. Collectively, our findings identify a potential mechanism by which GBM cells develop resistance to TMZ, and suggest that targeting the DNA damage tolerance pathway may be beneficial for overcoming resistance.