In this study we provide evidence that (a) PDK1 is a potential driver of osimertinib acquired resistance, (b) PDK1 genetic and pharmacological targeting restores osimertinib response in resistant clones and their derived human xenografts and PDXs, (c) PDK1 knock-out dysregulates PI3K/AKT/mTOR signaling and YAP activation, and (d) patient biopsies from EGFR mutant lung adenocarcinoma tumors with the highest PDK1 & YAP expression are found in a subset of patients with progressive disease following TKI treatment, suggesting they could be responsive to PDK1 inhibitors. The gene discussed is PDK1; the disease is lung adenocarcinoma.