Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma
Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma
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DOI：
10.18632/oncotarget.2720
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发表时间：
2015-03-30
期刊：
影响因子：
--
通讯作者：
Zinzani, Pier Luigi
中科院分区：
文献类型：
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作者：
Derenzini, Enrico;Agostinelli, Claudio;Zinzani, Pier Luigi
最近发现MYC驱动的癌症对抑制DNA损伤反应(DDR)通路敏感，这促使我们研究DDR通路作为弥漫性大B细胞淋巴瘤(DLBCL)治疗靶点的作用，DLBCL经常过度表达MYC癌基因。在对连续99例DLBCL患者进行的初步免疫组织化学研究中，我们发现大约一半的DLBCL细胞表达磷酸化形式的检查点蛋白(CHK)和CDC25c，它们是DDR激活的标志，以及磷酸化的组蛋白H_2AX(Gamma H_2AX)，它是DNA损伤和基因组不稳定的标志。组成性伽马H_2AX表达与c-myc水平和DDR激活相关，并定义了以预后不良为特征的肿瘤亚群。接下来，我们使用CHK抑制剂PF-0477736作为工具来研究抑制DDR通路是否可能代表DLBCL的一种新的治疗方法。亚微摩尔浓度的PF-0477736可抑制DDR途径激活的DLBCL细胞的增殖。用不同的CHK抑制剂(AZD-7762)完全概括了这些结果。抑制检查点蛋白激酶可诱导DLBCL细胞和原代细胞DNA损伤快速积累和凋亡。这些数据表明，通过靶向CHK激酶的药物抑制DDR可能是DLBCL的一种新的治疗策略。
The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (gamma H2AX), marker of DNA damage and genomic instability. Constitutive gamma H2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL.