Together, the results of this study highlight that pSTAT3 directly transactivates EGFR, which plays a critical role in maintaining EGFR protein homeostasis, and that the activation of pSTAT3-EGFR signaling is a novel molecular mechanism by which NSCLC cells develop acquired resistance to EGFR TKIs. Here, EGFR is linked to non-small cell lung carcinoma.