Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma

Cancer Biol Ther. 2014 Apr;15(4):380-8. doi: 10.4161/cbt.27623. Epub 2014 Jan 14.

Abstract

Malignant mesothelioma (MM) is a very aggressive asbestos-related neoplasm of the serous membranes, whose incidence is increasing worldwide. Although the introduction of new drug combinations, such as cisplatin plus pemetrexed/gemcitabine, has determined an improvement in the patient quality of life, MM remains a universally fatal disease. The observation that key G 1/S checkpoint regulators are often functionally inactivated in MM prompted us to test whether the use of G 2/M checkpoint inhibitors, able to sensitize G 1/S checkpoint-defective cancer cells to DNA-damaging agents, could be successful in MM. We treated six MM cell lines, representative of different histotypes (epithelioid, biphasic, and sarcomatoid), with cisplatin in combination with MK-1775, an inhibitor of the G 2/M checkpoint kinase WEE1. We observed that MK-1775 enhanced the cisplatin cytotoxic effect in all MM cell lines, except the sarcomatoid cell line, which is representative of the most aggressive histotype. As expected, the enhancement in cisplatin toxicity was accompanied by a decrease in the inactive phosphorylated form of cyclin-dependent kinase 1 (CDK1), a key substrate of WEE1, which is indicative of G 2/M checkpoint inactivation. Consistently, we also observed a decrease in G 2/M accumulation and an increase in mitotic entry of DNA-damaged cells and apoptosis, probably due to the loss of the cell ability to arrest cell cycle in response to DNA damage, irrespectively of p53 mutational status. Notably, this treatment did not increase cisplatin cytotoxicity on normal cells, thus suggesting a possible use of MK-1775 in combination with cisplatin for a safe and efficient treatment of epithelioid and biphasic MM.

Keywords: CDK1; G2/M checkpoint; MK-1775; WEE1; apoptosis; cisplatin; mesothelioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Drug Synergism
  • G2 Phase Cell Cycle Checkpoints*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Mesothelioma / drug therapy*
  • Mesothelioma / pathology
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology*
  • Pyrimidinones

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Pyrazoles
  • Pyrimidines
  • Pyrimidinones
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • adavosertib
  • Cisplatin

Supplementary concepts

  • Mesothelioma, Malignant