Sir Peter MacCallum Department of Oncology - Theses
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ItemOvercoming resistance to PI3K inhibitors in colorectal cancer( 2021)Colorectal cancer (CRC) is responsible for the second highest number of cancer deaths worldwide, with stage IV patients having a 5-year survival rate of only 14%. One of the treatments in development involves a targeted therapy directed at PI3K alpha, a protein mutated in 18% of CRC patients. Particularly, PI3K alpha is involved in several cancer hallmarks including survival, metabolism and migration. The introduction of PI3K inhibitors as targeted therapy in clinical trials caused an increase in overall survival and a decrease in disease progression. However, ultimately, treatment failure and tumour progression still occur due to development of drug resistance. Therefore, the aim of this project was to identify mechanisms of resistance to PI3K targeted therapy that can be exploited to overcome treatment failure. Specifically, the focus in this study is on BYL719, a PI3K alpha specific inhibitor. Firstly, a novel subcutaneous syngeneic mouse model of CRC was generated by the syngeneic transplant of Pik3ca mutated and Apc deleted gastrointestinal tumours from a mouse model of CRC. Tumour growth in this model was reduced upon treatment with BYL719. Mice were then chronically treated with BYL719 to induce resistance. Although the development of resistance was not confirmed within the time-frame of this thesis, this model proved to be a useful tool for pharmacological studies. Secondly, in silico analyses were performed, correlating the sensitivity of solid cancer cell lines to PI3K inhibition with CRISPR KO/mRNA/protein/metabolite data from online pharmacogenomic datasets. These analyses identified multiple pathways potentially involved with sensitivity to PI3K inhibition, including proteins involved in the regulation of the cytoskeleton, the PI3K/MAPK pathway, the endomembrane system and lipid and glutamine metabolism. Finally, an in vitro approach was performed using genome-wide CRISPR KO screen techniques, to identify additional functional pathways involved with sensitivity to PI3K inhibition. The results identified potential involvement of PI3K/Akt/MAPK signaling, mTOR/protein synthesis pathways, the Wnt pathway, TGF-beta pathway and metabolism, including lipids, glycolysis and the mitochondrial respiratory chain. Ultimately, these findings should enable the rational design of novel combination treatments with PI3K inhibitors to prevent or overcome resistance. Moreover, the findings might also be used to screen patients to predict their response to PI3K inhibitors.