The discovery of activating mutations within the epidermal growth factor gene (EGFR) and the clinical development of inhibitors specifically targeting the tyrosine kinase activity of mutated-EGFR has marked the advent of a new era of personalized medicine in lung cancer. The most common oncogenic mutations in the EGFR gene are deletions in exon19 and a missense mutation in exon 21 resulting in a single amino acid substitution. In vitro studies have demonstrated that EGFR mutations lead to increased and sustained autophosphorylation of EGFR and constitutive activation of antiapoptotic and proliferation signaling pathways. Adaptive resistance can lead a small subpopulation of EGFR mutant lung cancer cells to survive despite EGFR inhibition and eventually develop acquired resistance. A variety of feedback mechanisms have been described in patients with activating EGFR mutations receiving different classes of EGFR TKIs. Adaptive resistance to EGFR TKI therapy can develop through the activation of specific receptor tyrosine kinases (RTKs).
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