pSTAT3 transactivates EGFR in maintaining EGFR protein homeostasis and EGFR-TKI resistance

• Reduction in plasma membrane-associated EGFR triggers EGFR transcription via pSTAT3 nuclear localization, maintaining EGFR protein homeostasis. • Erlotinib promotes pSTAT3 nuclear accumulation, leading to increased EGFR transcription and acquired resistance to EGFR-TKIs. • Pharmacological inhibition of pSTAT3 significantly overcomes erlotinib resistance in cancer cells. • The pSTAT3-EGFR axis represents a novel molecular mechanism underlying EGFR-TKI resistance in non-small cell lung cancer.