Systematic Characterization of Recurrent Genomic Alterations in Cyclin-Dependent Kinases Reveals Potential Therapeutic Strategies for Cancer Treatment

Cell Rep. 2020 Jul 14;32(2):107884. doi: 10.1016/j.celrep.2020.107884.


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.

Keywords: CDK7 inhibitor; PARP inhibitor; cancer; combination therapy; cyclin-dependent kinase; genomic alteration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / genetics*
  • Cyclins / metabolism
  • DNA Copy Number Variations / genetics
  • DNA Damage / genetics
  • DNA Repair / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genome, Human*
  • Humans
  • Mice, Nude
  • Mutation / genetics*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplasms / genetics*
  • Neoplasms / therapy*
  • Phenylenediamines / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • Transcription, Genetic / drug effects


  • Antineoplastic Agents
  • Cyclins
  • Neoplasm Proteins
  • Phenylenediamines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyrimidines
  • THZ1 compound
  • Cyclin-Dependent Kinases