Functional annotation of oncogenic mutations in epidermal growth factor receptor kinase

The epidermal growth factor receptor (EGFR) kinase is activated by a variety of mutations in human cancer. Despite previous extensive research on EGFR, the structural and functional impact of the majority of cancer mutations remains poorly understood, hindered the effective treatment of patients harboring these mutations. In this dissertation, I establish a combined experimental and computational framework to investigate patient-derived mutations that map to the kinase domain of EGFR. First, I examine a recurrent R776H mutation and provide detailed mechanistic insight into EGFR signaling and kinase regulation. Next, I perform a mutation screening study focusing on the regulatory spine of EGFR. The study reveals a novel mode of kinase activation and drug resistance mechanism. Last, I characterize a class of less well-studied insertion mutations in the C-4 loop of the kinase domain. The findings presented in the dissertation not only shed light on mutation-mediated EGFR kinase activation, but also provide clues for patient treatment and future cancer drug design.