PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence

Oncogene. 2018 Sep;37(37):5066-5078. doi: 10.1038/s41388-018-0332-y. Epub 2018 May 23.


CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells. Materials from our previous phase II trials with palbociclib were then used to demonstrate that expression of CDH18 protein was associated with response, measured as both progression-free survival and overall survival. This supports the hypothesis that the biologic transition from quiescence to senescence has clinical relevance for this class of drugs.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Cellular Senescence / physiology*
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cytoskeletal Proteins / metabolism*
  • Disease-Free Survival
  • Humans
  • LIM Domain Proteins / metabolism*
  • Liposarcoma / drug therapy
  • Liposarcoma / metabolism
  • Piperazines / pharmacology
  • Progression-Free Survival
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Pyridines / pharmacology


  • Adaptor Proteins, Signal Transducing
  • CDH18 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • LIM Domain Proteins
  • PDLIM7 protein, human
  • Piperazines
  • Pyridines
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib