In conclusion, we presented multiple lines of evidence for PDK1 as a driver of osimertinib acquired resistance in T790M/L858R mutant NSCLC using the most relevant preclinical mouse models capable of modeling osimertinib acquired resistance We showed that pharmacological and genetic targeting of PDK1 could restore osimertinib responsiveness in cell lines and PDXs with acquired osimertinib resistance thus providing support for clinical translation. Here, PDK1 is linked to non-small cell lung carcinoma.