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

N. V. Rajeshkumar, Elizabeth De Oliveira, Niki Ottenhof, James Watters, David Brooks, Tim Demuth, Stuart D. Shumway, Shinji Mizuarai, Hiroshi Hirai, Anirban Maitra, Manuel Hidalgo

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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.

Original languageEnglish (US)
Pages (from-to)2799-2806
Number of pages8
JournalClinical Cancer Research
Volume17
Issue number9
DOIs
StatePublished - May 1 2011

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Rajeshkumar, N. V., De Oliveira, E., Ottenhof, N., Watters, J., Brooks, D., Demuth, T., Shumway, S. D., Mizuarai, S., Hirai, H., Maitra, A., & Hidalgo, M. (2011). MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clinical Cancer Research, 17(9), 2799-2806. https://doi.org/10.1158/1078-0432.CCR-10-2580