Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy
Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy
复制标题
纺锤体组装检查点抑制可以使p53-p53干细胞对癌症化疗重新敏感
DOI：
10.1158/0008-5472.can-18-3024
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发表时间：
2019-05-01
期刊：
影响因子：
11.2
通讯作者：
Buckhaults, Phillip J.
中科院分区：
文献类型：
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作者：
Liu, Changlong;Banister, Carolyn E.;Buckhaults, Phillip J.
TP 53突变在大多数人类癌症中很常见，但针对TP 53突变肿瘤的治疗选择很少。为了确定具有TP 53突变的癌症患者的潜在治疗选择，我们分析了127种FDA批准的针对人胚胎干细胞（hESC）的化疗药物，其中我们通过基因组编辑工程化TP 53缺失。我们确定了27种TP 53突变赋予耐药性的癌症治疗药物;这些药物中的大多数靶向DNA合成或拓扑异构酶并导致DNA损伤。然后，我们在存在和不存在亚致死浓度的顺铂的情况下，在TP 53-null hESC中进行了全基因组CRISPR/Cas9敲除筛选，并鉴定了137个基因，其损失选择性地使p53-null细胞对这种化疗剂重新敏感。再致敏位点的基因本体分类揭示了纺锤体检查点途径基因的显著过度表达。此外，我们证实靶向ZNF 207/BuGZ可使p53缺失的hESC对顺铂敏感。这些数据表明，纺锤体组装检查点（SAC）和染色体组织中心的靶向抑制可能提供一种用标准化疗药物治疗p53缺陷癌细胞的方法。SAC蛋白的小分子抑制剂的发展可能是一个有用的策略，拯救DNA损伤化疗药物在TP 53-突变cancers.Significance：这些研究结果表明，抑制纺锤体组装检查点和染色体组织中心可能提供了一种新的方式来治疗p53缺陷的癌细胞与标准化疗药物。
TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDA-approved chemotherapy drugs against human embryonic stem cells (hESC) in which we engineered TP53 deletion by genome editing. We identified 27 cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis or topoisomerase and cause DNA damage. We then performed a genome-wide CRISPR/Cas9 knockout screen in the TP53-null hESC in the presence and absence of sublethal concentrations of cisplatin and identified 137 genes whose loss selectively resensitized the p53-null cells to this chemotherapeutic agent. Gene ontology classification of the resensitizing loci revealed significant overrepresentation of spindle checkpoint pathway genes. Moreover, we confirmed that targeting ZNF207/BuGZ sensitizes p53-null hESC to cisplatin. These data indicate that targeted inhibition of spindle assembly checkpoints (SAC) and chromosomal organizing centers may provide a way to treat p53-deficient cancer cells with standard chemotherapy drugs. Development of small-molecule inhibitors of SAC proteins may be a useful strategy for rescuing DNA-damaging chemotherapeutics in TP53-mutant cancers.Significance: These findings show that inhibition of spindle assembly checkpoints and chromosomal organizing centers may provide a new way to treat p53-deficient cancer cells with standard chemotherapy drugs.