MK-1775, a Potent Wee1 Inhibitor, Synergizes with Gemcitabine to Achieve Tumor Regressions, Selectively in p53-Deficient Pancreatic Cancer Xenografts

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Clinical Cancer Research (Impact Factor: 8.72). 03/2011; 17(9):2799-806. DOI: 10.1158/1078-0432.CCR-10-2580
Source: PubMed


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

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    • "When tumors reached a volume of 500 mm3, mice were individually identified and randomly assigned to treatment groups of 4 mice (6–8 evaluable tumors) in each group: 1) control; 2) MK-1775 (30 mg/kg p.o., twice daily on days 1, 3, 8, and 10); 3) gemcitabine (100 mg/kg i.p., once daily on days 1, 3, 8, 10); or 4) MK-1775 and gemcitabine in the above-mentioned doses. Drug doses and schedules were chosen based on the investigator brochure, findings of an ASCO abstract phase I preliminary study and prior studies [10], [16]. Tumor growth was evaluated twice per week by measurement of two perpendicular diameters of tumors with a digital caliper. "
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