H. Lee Moffitt Cancer Center and Research Institute Tampa United States
Central to all cycling cells-including prostate cancer stem cells- is the expression of WEE1 tyrosine kinase. WEE1 monitors duplication of the chromatin during each cell cycle to preserve genome stability and prevent mitotic catastrophe. PTEN phosphatase and tensin homolog is deleted at the 10q23.3 locus in 40 of human prostate cancers and is associated with aggressive metastatic disease with poor prognosis and androgen-independence. A PTEN null prostate cancer derived cell line, LNCaP, displays hypersensitivity and under goes significant cell death in response to treatment with the WEE1 inhibitor, MK1775. In contrast to LNCaP, MK1775 induces a differentiation like phenotype in the PTEN wild type prostate cancer derived cell line, LAPC4. Our hypothesis is that PTEN deletion results in hyper-proliferation phenotype in part due to the constitutive activation of the oncogenic AKT survival kinase and these cells requireWEE1 to ensure proper chromatin duplication. However, blocking WEE1 function, will force cells to enter mitosis with incompletely replicated chromatin leading to mitotic catastrophe. In contrast, LAPC4 cells, with regulated AKT activation will respond to WEE1inhibition by undergoing arrest at the G2M border. This proposal will explore WEE1 kinase as a novel therapeutic target in PTEN mutated prostate cancer.