One of the driver mutations frequently found in lung adenocarcinoma patients is a mutation that constitutively activates the epidermal growth factor receptor (EGFR). Patients with EGFR-driven tumors benefit substantially from treatment with tyrosine kinase inhibitors (TKIs) like osimertinib. Inevitably, all patients develop resistance mechanisms against TKIs. Activation of alternative signaling pathways seems to be a major driver of acquired resistance against targeted inhibition of EGFR in lung cancer patients. At the same time co-existing EGFR and MAPK mutations are thought to be mutually exclusive and potentially augment the cellular stress levels beyond a tolerable threshold. By establishing a CRISPR-based search-and-replace genome editing method I will be able to characterize MAPK-driven resistance signaling and quantitatively compare the activation of MAPK signaling at different levels of the cascade. This approach may enable us to define effective combination therapies for this subgroup of EGFR inhibitor resistant patients.