Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors.Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.Mitogen Activated Protein Kinase (MAPK) pathways are at the heart of molecular signalling networks that govern the growth, proliferation, differentiation and survival of many, if not all, cell types [1]. MAPK pathways are deregulated in various diseases ranging from cancer to immunological, inflammatory and degenerative syndromes, and thus represent increasingly important drug targets. Perhaps the most important and intensively studied MAPK pathway is the Extracellular-signal Regulated Kinase (ERK) pathway, which is typically initiated by the ac