The tumor suppressor gene ATRX is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro, as well as xenografts in vivo. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage-induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX. SIGNIFICANCE: ATRX-mutant cancer cells depend on WEE1, which provides a basis for therapeutically targeting WEE1 in ATRX-deficient cancers.See related commentary by Cole, p. 375.

中文翻译：

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全基因组CRISPR-Cas9屏幕揭示了ATRX突变型癌症对WEE1抑制的选择性脆弱性。

肿瘤抑制基因ATRX经常在包括神经胶质瘤和肝癌在内的多种肿瘤中发生突变，这些肿瘤对目前的疗法高度无反应。在这里，我们使用CRISPR-Cas9基因组编辑进行了全基因组合成致死筛选，以鉴定特异于ATRX突变癌症的潜在治疗靶标。在专为ATRX缺失而设计的等基因肝细胞癌（HCC）细胞系中，我们鉴定了58个基因，包括检查点激酶WEE1，这对于ATRX空细胞的细胞生长是唯一需要的。使用WEE1抑制剂AZD1775进行的治疗在体外以及体内异种移植物中均能强烈抑制几种ATRX缺陷型HCC细胞系的生长。对WEE1抑制剂的敏感性增加是由累积的DNA损伤诱导的细胞凋亡引起的。AZD1775还可以选择性抑制具有自然发生ATRX突变的神经胶质瘤患者来源的原代细胞系的增殖，这表明WEE1和ATRX之间的合成致死关系可以在更广泛的人类肿瘤中得到利用。由于WEE1抑制剂已在多个II期临床试验中进行了研究，因此我们的发现为针对ATRX缺乏的癌症的易于临床测试的治疗策略提供了基础。意义：ATRX突变的癌细胞依赖WEE1，这为在ATRX缺乏的癌症中治疗性靶向WEE1提供了基础。375。这表明WEE1和ATRX之间的合成致死关系可以在更广泛的人类肿瘤中得到利用。由于WEE1抑制剂已在多个II期临床试验中进行了研究，因此我们的发现为针对ATRX缺乏的癌症的易于临床测试的治疗策略提供了基础。意义：ATRX突变的癌细胞依赖WEE1，这为在ATRX缺乏的癌症中治疗性靶向WEE1提供了基础。375。这表明WEE1和ATRX之间的合成致死关系可以在更广泛的人类肿瘤中得到利用。由于WEE1抑制剂已在数个II期临床试验中进行了研究，因此我们的发现为针对ATRX缺乏的癌症的易于临床测试的治疗策略提供了基础。意义：ATRX突变的癌细胞依赖WEE1，这为在ATRX缺乏的癌症中治疗性靶向WEE1提供了基础。375。这为在ATRX缺乏的癌症中靶向治疗WEE1提供了基础。375。这为在ATRX缺乏的癌症中靶向治疗WEE1提供了基础。375。