Abstract

Dysregulation in processes such as growth, migration and differentiation in cancer cells is often a result of mutations in proto-oncogenes or oncogenes of the cellular signalling pathway. Cancer cells often become dependent on the activity of such oncogenes, making these oncogenes potential drug targets. While effective, pharmacological interventions of oncogenes are often limited by adaptive resistance which is often a result of ‘rewiring’ of the signalling pathways that allows bypass of the drug inhibited. Understanding the principles of the signal rewiring and identification of players in this process will have profound implications in improving current therapeutic interventions. Here, a number of CRISPR -based approaches is being utilised to dissect the players that govern signal dysregulation mainly in the context of melanoma. Dr Evangelia Petsalaki will describe a computational framework they have recently devised that uses publicly available essentiality screens performed in on ~500 cell lines to interrogate the ‘context’ of a context specific gene. The tool was applied to identify the essentiality of signalling related genes in melanoma, which provides clues to cell-specific signalling pathways used by melanoma cells with a range of mutational backgrounds and drug response profiles. Dr Petsalaki will also discuss their recent efforts to combine arrayed CRISPR -based genetic perturbation with phospho-proteomic measurements to identify pathway cross-talks in the context of resistance to MAPK pathway inhibitors in BRAFV600E melanoma. The results from this project will contribute to better understanding of the principles of cell signalling rewiring in cancer progression and drug resistance.