Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer
Genome-Wide Identification and Characterization of Novel Factors Conferring Resistance to Topoisomerase II Poisons in Cancer
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DOI：
10.1158/0008-5472.can-15-0380
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发表时间：
2015-10-01
期刊：
影响因子：
11.2
通讯作者：
Neefjes, Jacques
中科院分区：
文献类型：
--
作者：
Wijdeven, Ruud H.;Pang, Baoxu;Neefjes, Jacques
拓扑异构酶II的毒药阿霉素和依托泊苷构成长期的化疗的基石。尽管它们广泛的临床应用，但许多患者对这些药物没有反应。使用全基因组基因敲除方法，我们将Keap 1、SWI/SNF复合物和C9 orf 82（CAAP 1）确定为能够通过不同分子机制驱动耐药性的独立因素，所有这些因素都集中在DNA双链断裂（DSB）和修复途径上。Keap 1或SWI/SNF复合物的缺失分别通过减弱拓扑异构酶II α的表达和活性来抑制DSB的产生，而C9 orf 82的缺失则增强随后的DSB修复。它们相应的基因在人类肿瘤中经常突变或缺失，可能会影响药物敏感性，例如SWI/SNF核心成员表达减少的三阴性乳腺癌患者对含阿霉素的化疗方案的反应性降低。总的来说，我们的工作确定了可以预测癌症患者对广泛使用的拓扑异构酶II毒药的反应的基因，并确定了可用于治疗耐药患者的替代途径。(C)2015年AACR。
The topoisomerase II poisons doxorubicin and etoposide constitute longstanding cornerstones of chemotherapy. Despite their extensive clinical use, many patients do not respond to these drugs. Using a genome-wide gene knockout approach, we identified Keap1, the SWI/SNF complex, and C9orf82 (CAAP1) as independent factors capable of driving drug resistance through diverse molecular mechanisms, all converging on the DNA double-strand break (DSB) and repair pathway. Loss of Keap1 or the SWI/SNF complex inhibits generation of DSB by attenuating expression and activity of topoisomerase II alpha, respectively, whereas deletion of C9orf82 augments subsequent DSB repair. Their corresponding genes, frequently mutated or deleted in human tumors, may impact drug sensitivity, as exemplified by triple-negative breast cancer patients with diminished SWI/SNF core member expression who exhibit reduced responsiveness to chemotherapy regimens containing doxorubicin. Collectively, our work identifies genes that may predict the response of cancer patients to the broadly used topoisomerase II poisons and defines alternative pathways that could be therapeutically exploited in treatment-resistant patients. (C) 2015 AACR.