The combined status of ATM and p53 link tumor development with therapeutic response
The combined status of ATM and p53 link tumor development with therapeutic response
复制标题
DOI：
10.1101/gad.1815309
复制
发表时间：
2009-08-15
影响因子：
10.5
通讯作者：
Hemann, Michael T.
中科院分区：
文献类型：
--
作者：
Jiang, Hai;Reinhardt, H. Christian;Hemann, Michael T.
虽然特定肿瘤抑制网络对癌症发展的贡献一直是最近大量研究的主题，但仍不清楚这些网络中的改变如何整合以影响肿瘤对抗癌治疗的反应。在这里，我们表明，肿瘤通常用于绕过早期肿瘤检查点的机制最终决定化疗反应，并产生可用于靶向治疗的肿瘤特异性脆弱性。具体而言，ATM和p53，两个常见的突变的肿瘤抑制基因的组合状态的评估，可以帮助预测遗传毒性化疗的临床反应。我们发现，在p53缺陷的情况下，ATM的抑制显着敏感肿瘤DNA损伤化疗，而相反，在功能性p53的存在下，ATM或其下游靶Chk 2的抑制实际上保护肿瘤被杀死的遗传毒性剂。此外，ATM缺陷型癌细胞显示出对DNA-PKcs的强非癌基因成瘾性，以便在DNA损伤后存活，使得DNA-PKcs在体内的抑制使固有的化学抗性ATM缺陷型肿瘤对遗传毒性化学疗法重新敏感。因此，在肿瘤发展过程中诱导的特定改变集在确定给定恶性肿瘤中对常规化疗的肿瘤反应和对靶向治疗的特定敏感性方面起主导作用。
While the contribution of specific tumor suppressor networks to cancer development has been the subject of considerable recent study, it remains unclear how alterations in these networks are integrated to influence the response of tumors to anti-cancer treatments. Here, we show that mechanisms commonly used by tumors to bypass early neoplastic checkpoints ultimately determine chemotherapeutic response and generate tumor-specific vulnerabilities that can be exploited with targeted therapies. Specifically, evaluation of the combined status of ATM and p53, two commonly mutated tumor suppressor genes, can help to predict the clinical response to genotoxic chemotherapies. We show that in p53-deficient settings, suppression of ATM dramatically sensitizes tumors to DNA-damaging chemotherapy, whereas, conversely, in the presence of functional p53, suppression of ATM or its downstream target Chk2 actually protects tumors from being killed by genotoxic agents. Furthermore, ATM-deficient cancer cells display strong nononcogene addiction to DNA-PKcs for survival after DNA damage, such that suppression of DNA-PKcs in vivo resensitizes inherently chemoresistant ATM-deficient tumors to genotoxic chemotherapy. Thus, the specific set of alterations induced during tumor development plays a dominant role in determining both the tumor response to conventional chemotherapy and specific susceptibilities to targeted therapies in a given malignancy.