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- W2001878144 abstract "In Australia melanomas account for 10% of all reported cancers and 3% of cancer mortalities. Current treatments offer Using ICRF-193, an inhibitor of Topoisomerase II, a panel of melanoma cell lines were investigated for decatenation checkpoint function. This analysis revealed that 17/25 melanoma cell lines possessed a defective decatenation checkpoint, suggesting it to be a common defect. Treatment with ICRF-193 caused checkpoint defective cells to undergo an aberrant mitosis, resulting in accumulation of cells exhibiting abnormal nuclear morphologies, while checkpoint functional cells remained relatively unaffected. Comparative gene expression analysis revealed differential expression of cell-division and cell-death associated genes, suggesting adaptive changes compensating for checkpoint failure. A strong gene-expression signature for the checkpoint defect was also observed in this analysis and potential bio-markers are being investigated for use identifying this defect in tumors. A synthetic lethality siRNA screen of the kinome (∼700 genes) was carried out to identify genes/pathways crucial to the viability of cell lines with a defective decatentation checkpoint. This screen identified 10 potential hits, many involved in PI3Kinase signaling. We have validated this pathway as a selective target. This research has shown that the defective decatenation checkpoint is a viable target in melanoma. Using targets identified by the synthetic lethality screens and bio-markers to the defect in tumors, it should be possible to identify tumors most likely to be sensitive to drugs targeting the checkpoint defect, providing effective and selective therapeutics for the treatment of metastatic melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A65." @default.
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- W2001878144 date "2011-11-12" @default.
- W2001878144 modified "2023-09-25" @default.
- W2001878144 title "Abstract A65: Targeting the defective decatenation checkpoint in melanoma." @default.
- W2001878144 doi "https://doi.org/10.1158/1535-7163.targ-11-a65" @default.
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