Exploring the Hypersensitivity of PTEN Deleted Prostate Cancer Stem Cells to WEE1 Tyrosine Kinase Inhibitors
Abstract
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 undergoes 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 wildtype 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 require WEE1 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 WEE1 inhibition by undergoing arrest at the G2/M border. This proposal will explore WEE1 kinase as a novel therapeutic target in PTEN mutated prostate cancer. The main objectives are to first examine WEE1 nuclear signaling in isogenic PTEN-deficient and proficient prostate cancer cell lines and prostate cancer stem cell population. Second, interrogate whether PTEN depleted prostate cancer stem cells (PCSC) display enhanced sensitivity to WEE1 inhibitors. Finally, determine whether WEE1 inhibitors prevent tumorigenic potential of PCSC and block metastasis of PTEN null prostate xenograft tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2015
- Accession Number
- ADA631862
Entities
People
- Kiran Mahajan
Organizations
- H. Lee Moffitt Cancer Center & Research Institute