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

Resistance to chemo- and radiotherapy through alterations in the apoptotic pathway
frequently 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 cancer
cells to apoptosis and reduce this problem. However, these therapies show a lack of
efficacy in a large proportion of the patient population and cancer cell lines. This PhD
project aims to uncover the biomarkers for IAP antagonist sensitivity, understand the
mechanisms of sensitivity as well as identify alternative and more ubiquitous targets. In
order to achieve this, the project will be split into three phases: target and biomarker
identification, target validation and drug design. Initially, breast and pancreatic cancer cell
lines are being categorised as sensitive or resistant to LCL161 and Birinapant (IAP
antagonists). Then a genome-wide CRISPR screen will be performed in both categories
with exposure to the IAP antagonists. This will allow us to identify potential sensitisation
and resistance genes which could be effective targets or biomarkers. In parallel,
bioinformatics analysis of existing shRNA enrichment studies is being used to confirm and
complement the project's findings. Overall, this research aims to contribute towards
providing better treatment alternatives to patients who have developed chemo- or
radiotherapy resistant tumours.