Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib
Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib
复制标题
DOI：
10.1016/j.ccell.2017.11.006
复制
发表时间：
2017-12-11
期刊：
影响因子：
50.3
通讯作者：
Buchanan, Sean G.
中科院分区：
文献类型：
--
作者：
Gong, Xueqian;Litchfield, Lacey M.;Buchanan, Sean G.
大多数癌症保留功能性视网膜母细胞瘤 (Rb)，因此可能对 D-细胞周期蛋白依赖性 Rb 激酶、CDK4 和 CDK6 的抑制有反应。迄今为止，CDK4/6 抑制剂已在乳腺癌和淋巴瘤中显示出有希望的临床活性，但尚不清楚哪些其他 Rb 阳性癌症可能受益于这些药物。尚未描述比较不同肿瘤类型的相对敏感性和定义反应的分子决定因素的系统调查。我们报告了一组对 CDK4/6 抑制高度敏感的癌症，其特征是已知可提高 D-细胞周期蛋白水平的各种基因组畸变，并描述了与子宫内膜癌表达增加相关的复发性 CCND1 3'UTR 突变。结果表明，多种其他类型的癌症可能受益于 abemaciclib 等 CDK4/6 抑制药物。
Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib.