Systematic Characterization of Recurrent Genomic Alterations in Cyclin-Dependent Kinases Reveals Potential Therapeutic Strategies for Cancer Treatment
Weiwei Shan,
Jiao Yuan,
Zhongyi Hu,
Junjie Jiang,
Yueying Wang,
Nicki Loo,
Lingling Fan,
Zhaoqing Tang,
Tianli Zhang,
Mu Xu,
Yutian Pan,
Jiaqi Lu,
Meixiao Long,
Janos L. Tanyi,
Kathleen T. Montone,
Yi Fan,
Xiaowen Hu,
Youyou Zhang,
Lin Zhang
Affiliations
Weiwei Shan
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA
Jiao Yuan
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Zhongyi Hu
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Junjie Jiang
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Yueying Wang
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Nicki Loo
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Lingling Fan
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Zhaoqing Tang
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Tianli Zhang
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Mu Xu
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Yutian Pan
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Jiaqi Lu
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA
Meixiao Long
Department of Internal Medicine, Division of Hematology, Ohio State University, Columbus, OH 43210, USA
Janos L. Tanyi
Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA
Kathleen T. Montone
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Yi Fan
Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA
Xiaowen Hu
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA
Youyou Zhang
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Lin Zhang
Center for Research on Reproduction & Women’s Health, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Summary: 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, CDK12 exhibits recurrent mutations in multiple cancers. Among the transcriptional CDKs, CDK7 and CDK12 show 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.
