Mechanism-based Drug Discovery. (360G-Wellcome-102359_Z_13_Z)

The first aim of the project is determine those cancer types that are sensitive to single agent CHK1 inhibition and identify potential biomarkers of this phenotype,such as replication stress (RS). CHK1i have shown single agent activity in certain cancer types, including neuroblastoma and B cell lymphoma, the literature suggests this may be due to increased replication stress. Which leads on to the second aim of the project,which is to establish models of RS to determine if it enhances single agent CHK1 sensitivity. This will be done looking a t foci indicative of replication stress. Finally, the Iast aim of the project is toidentify those gene products whose loss is synthetically lethal with CHK1 inhibition in cancer cells, which could allow the therapeutic activity of CHK1 inhibitors to be broadened through use with appropriate molecularly targeted agents. This will be done by screening 2 CHK1i resistant cell lines, with and without CHK1i,aqainst the Dharmacon druqqable qenome siRNA library.