MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts

Clin Cancer Res. 2011 May 1;17(9):2799-806. doi: 10.1158/1078-0432.CCR-10-2580. Epub 2011 Mar 9.

Abstract

Purpose: Investigate the efficacy and pharmacodynamic effects of MK-1775, a potent Wee1 inhibitor, in both monotherapy and in combination with gemcitabine (GEM) using a panel of p53-deficient and p53 wild-type human pancreatic cancer xenografts.

Experimental design: Nine individual patient-derived pancreatic cancer xenografts (6 with p53-deficient and 3 with p53 wild-type status) from the PancXenoBank collection at Johns Hopkins were treated with MK-1775, GEM, or GEM followed 24 hour later by MK-1775, for 4 weeks. Tumor growth rate/regressions were calculated on day 28. Target modulation was assessed by Western blotting and immunohistochemistry.

Results: MK-1775 treatment led to the inhibition of Wee1 kinase and reduced inhibitory phosphorylation of its substrate Cdc2. MK-1775, when dosed with GEM, abrogated the checkpoint arrest to promote mitotic entry and facilitated tumor cell death as compared to control and GEM-treated tumors. MK-1775 monotherapy did not induce tumor regressions. However, the combination of GEM with MK-1775 produced robust antitumor activity and remarkably enhanced tumor regression response (4.01-fold) compared to GEM treatment in p53-deficient tumors. Tumor regrowth curves plotted after the drug treatment period suggest that the effect of the combination therapy is longer-lasting than that of GEM. None of the agents produced tumor regressions in p53 wild-type xenografts.

Conclusions: These results indicate that MK-1775 selectively synergizes with GEM to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Line, Tumor
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Disease Progression
  • Drug Synergism
  • Female
  • Gemcitabine
  • Genes, p53
  • Humans
  • Mice
  • Mice, Nude
  • Mutation / physiology
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Nuclear Proteins / antagonists & inhibitors
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrazoles / administration & dosage*
  • Pyrazoles / pharmacology
  • Pyrimidines / administration & dosage*
  • Pyrimidines / pharmacology
  • Pyrimidinones
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Cell Cycle Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Pyrimidinones
  • Deoxycytidine
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • adavosertib
  • Gemcitabine