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- W2326458051 abstract "Wee1 is a major regulator of mitotic entry. It phosphorylates and inactivates CDC2/ CDK1, and its functional role is considered to be in G 2 checkpoint signaling. MK-1775, a potent and selective small molecular inhibitor of Wee1 kinase, has been recently shown to have activity sensitizing to DNA-damaging agents and radiotherapy in p53 deficient human tumor cells. To further understand the underlying mechanism and the therapeutic potential to target Wee1 in pancreatic cancer, we investigated MK1775 in patient-derived pancreatic cancer xenografts grown orthotopically, and primary pancreatic cancer cells. MK-1775 treatment significantly reduced phosphorylation of CDC2 at Tyr15 and induced phosphorylated histone H3 in a dose- and time-dependent manner, consistent with the effect on G 2 checkpoint. Single DNA content histogram showed a population accumulating in the early S phase following MK-1775 treatment, suggesting that this compound may have additional cell cycle effect besides G 2 . γ-H2AX accumulated in early to mid S phase following MK-1775 treatment in vitro, consistent with a recent report that wee1 depletion induces DNA damage in newly replicated DNA (J Cell Biol 2010; 188: 629-38). Furthermore, MK-1775 treatment produced increased cyclin A2, cyclin B1, Aurora A kinase, and phosphorylated histone H3 population in the early S phase detected by multiparametric flow cytometry. Consistently, chromosome condensation and dispersal of lamin B1 into the cytoplasm were observed following Wee1 inhibition using confocal microscopy, suggesting that MK-1775 triggers premature mitosis in vitro. Infection of a series of lentiviral shRNAs targeting Wee1 showed similar results as MK-1775. CDK2 and CDC2/ CDK1 show structural similarities, and both are phosphorylated at Tyr15 by wee1, which might explain the S phase effects following wee1 inhibition. Administration of MK-1775 in vivo also showed accumulating γ-H2AX in mid to late S phase and increased phosphorylated histone H3, but no obvious early S phase effects were observed. Combination of MK1775 with gemcitabine showed enhanced anticancer effect in orthotopic primary pancreatic cancer xenografts. These data support targeting wee1 in pancreatic cancer patients, and suggest that the wee1 inhibitor MK1775 has cell cycle effects additional to G 2 checkpoint control that are relevant to the further development of drug combinations. Citation Format: Qing Chang, Jason Moffat, David W. Hedley. Targeting Wee1 in primary pancreatic cancer xenografts. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A26." @default.
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- W2326458051 date "2012-07-15" @default.
- W2326458051 modified "2023-09-24" @default.
- W2326458051 title "Abstract A26: Targeting Wee1 in primary pancreatic cancer xenografts." @default.
- W2326458051 doi "https://doi.org/10.1158/1538-7445.panca2012-a26" @default.
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