MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells

Mol Cancer Ther. 2012 Jan;11(1):174-82. doi: 10.1158/1535-7163.MCT-11-0529. Epub 2011 Nov 14.

Abstract

Wee1 is a critical component of the G(2)-M cell-cycle checkpoint control and mediates cell-cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by a selective small molecule inhibitor MK1775 can abrogate G(2)-M checkpoint, resulting in premature mitotic entry and cell death. MK1775 has recently been tested in preclinical and clinical studies of human carcinoma to enhance the cytotoxic effect of DNA-damaging agents. However, its role in mesenchymal tumors, especially as a single agent, has not been explored. Here, we studied the cytotoxic effect of MK1775 in various sarcoma cell lines and patient-derived tumor explants ex vivo. Our data show that MK1775 treatment at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. In MK1775-treated cells, CDC2 activity was enhanced, as determined by decreased inhibitory phosphorylation of tyrosine-15 residue and increased expression of phosphorylated histone H3, a marker of mitotic entry. The cytotoxic effect of Wee1 inhibition on sarcoma cells seems to be independent of p53 status as all sarcoma cell lines with different p53 mutation were highly sensitive to MK1775 treatment. Finally, in patient-derived sarcoma samples, we showed that MK1775 as a single agent causes significant apoptotic cell death, suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • CDC2 Protein Kinase
  • Cell Cycle Checkpoints / drug effects*
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin B / metabolism
  • Cyclin-Dependent Kinases
  • Histones / metabolism
  • Humans
  • Mitosis / drug effects*
  • Nuclear Proteins / antagonists & inhibitors*
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology*
  • Pyrimidinones
  • Sarcoma / pathology*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Cyclin B
  • Histones
  • Nuclear Proteins
  • Pyrazoles
  • Pyrimidines
  • Pyrimidinones
  • Tumor Suppressor Protein p53
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • Cyclin-Dependent Kinases
  • adavosertib