A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers
A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers
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DOI：
10.1016/j.ccell.2020.03.004
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发表时间：
2020-05-11
期刊：
影响因子：
50.3
通讯作者：
Cichowski, Karen
中科院分区：
文献类型：
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作者：
Guerra, Stephanie L.;Maertens, Ophelia;Cichowski, Karen
虽然KRAS突变在非小细胞肺癌(NSCLC)中很常见，但缺乏有效的治疗方法。在这里，我们报告了一半的KRAS突变的NSCLC异常表达同源盒蛋白HOXC10，这主要是由于PRC2中未被意识到的缺陷，这使得在异种移植和PDX模型中对BET/MEK联合抑制剂敏感。联合用药的疗效取决于BET抑制剂对HOXC10的抑制作用。我们进一步证明HOXC10在敏感肿瘤中调节复制前复合体(Pre-RC)蛋白的表达。因此，BET/MEK抑制剂抑制循环细胞中的前RC蛋白，引发复制停滞、DNA损伤和死亡。这些研究揭示了一种有前景的治疗KRAS突变的非小细胞肺癌的策略，识别了一个可预测反应的生物标志物，并定义了具有靶向性表观遗传易感性的非小细胞肺癌的子集。
While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatments are lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein HOXC10, largely due to unappreciated defects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograft and PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replication complex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppress pre-RC proteins in cycling cells, triggering stalled replication, DNA damage, and death. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset of NSCLCs with a targetable epigenetic vulnerability.