EGFR activating mutations are present in 10-40% of non-small cell lung cancer. Such mutations render tumour cells sensitive to EGFR tyrosine kinase inhibitors (EGFR TKIs), with responses of up to 80% in populations selected for the presence of an activating mutation. Unfortunately, almost all patients develop resistance after about a year. Clinically described mechanisms of resistance include the presence of a secondary mutation (T790M) in EGFR which prevents EGFR TKIs binding to the EGF receptor, and amplification MET which permits survival signalling via the ERBB3 receptor. However in 30% of cases, the mechanism of acquired resistance to EGFR TKIs is still unknown. My aim was to carry out a genome-wide siRNA screen to identify novel mechanisms of resistance to EGFR TKIs. I identified two genes that have not been implicated in EGFR TKI resistance previously, NF1 and DEPTOR, which are negative regulators of RAS and mTOR respectively. Depletion of NF1 or DEPTOR leads to increased resistance to EGFR TKIs via upregulation of MAPK signalling by direct and indirect mechanisms.