Systematic Characterization of Recurrent Genomic Alterations in Cyclin-Dependent Kinases Reveals Potential Therapeutic Strategies for Cancer Treatment.
Systematic Characterization of Recurrent Genomic Alterations in Cyclin-Dependent Kinases Reveals Potential Therapeutic Strategies for Cancer Treatment.
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DOI：
10.1016/j.celrep.2020.107884
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发表时间：
2020-07
期刊：
影响因子：
8.8
通讯作者：
Weiwei Shan;Jiao Yuan;Zhongyi Hu;Junjie Jiang;Yueying Wang;Nicki Loo;L. Fan;Zhaoqing Tang;Tianli Zhang;Mu Xu;Yutian Pan;J. Lu;M. Long;J. Tanyi;K. Montone;Yi Fan;Xiaowen Hu;Youyou Zhang;Lin Zhang
中科院分区：
文献类型：
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作者：
Weiwei Shan;Jiao Yuan;Zhongyi Hu;Junjie Jiang;Yueying Wang;Nicki Loo;L. Fan;Zhaoqing Tang;Tianli Zhang;Mu Xu;Yutian Pan;J. Lu;M. Long;J. Tanyi;K. Montone;Yi Fan;Xiaowen Hu;Youyou Zhang;Lin Zhang
Recurrent copy-number alterations, mutations, and transcript fusions of the genes encoding CDKs/cyclins are characterized in >10,000 tumors. Genomic alterations of CDKs/cyclins are dominantly driven by copy number aberrations. In contrast to cell-cycle-related CDKs/cyclins, which are globally amplified, transcriptional CDKs/cyclins recurrently lose copy numbers across cancers. Although mutations and transcript fusions are relatively rare events,CDK12exhibits recurrent mutations in multiple cancers. Among the transcriptional CDKs,CDK7andCDK12show the most significant copy number loss and mutation, respectively. Their genomic alterations are correlated with increased sensitivities to DNA-damaging drugs. Inhibition of CDK7 preferentially represses the expression of genes in the DNA-damage-repair pathways and impairs the activity of homologous recombination. Low-dose CDK7 inhibitor treatment sensitizes cancer cells to PARP inhibitor-induced DNA damage and cell death. Our analysis provides genomic information for identification and prioritization of drug targets for CDKs and reveals rationales for treatment strategies.
