Article

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

ABSTRACT

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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    • "Given the critical role of WEE1 in regulating the cellular response to DNA damage, WEE1 is a promising target for cancer therapy [13]. The small-molecule WEE1 inhibitor AZD1775 is a first-in-class agent that has shown anticancer activity both alone and in combination with radiation and chemotherapy in preclinical studies [14] [15] [16] [17]. Many clinical trials (phase 1 and 2) are under way combining AZD1775 with radiation, chemotherapy, and chemoradiation for several disease sites including cancers of the head and neck, lung, ovary, cervix, and pancreas as well as diffuse intrinsic pontine glioma and glioblastoma. "
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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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