Identifying the molecular basis for resistance to apoptosis in breast and pancreatic cancer

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Resistance to chemo- and radiotherapy through alterations in the apoptotic pathwayfrequently result in patients being unable to benefit from traditional treatments. Currently,there are several IAP antagonist in the clinical trial pipeline which hope to sensitise cancercells to apoptosis and reduce this problem. However, these therapies show a lack ofefficacy in a large proportion of the patient population and cancer cell lines. This PhDproject aims to uncover the biomarkers for IAP antagonist sensitivity, understand themechanisms of sensitivity as well as identify alternative and more ubiquitous targets. Inorder to achieve this, the project will be split into three phases: target and biomarkeridentification, target validation and drug design. Initially, breast and pancreatic cancer celllines are being categorised as sensitive or resistant to LCL161 and Birinapant (IAPantagonists). Then a genome-wide CRISPR screen will be performed in both categorieswith exposure to the IAP antagonists. This will allow us to identify potential sensitisationand resistance genes which could be effective targets or biomarkers. In parallel,bioinformatics analysis of existing shRNA enrichment studies is being used to confirm andcomplement the project's findings. Overall, this research aims to contribute towardsproviding better treatment alternatives to patients who have developed chemo- orradiotherapy resistant tumours.