Enhanced Efficacy of EGFR-Targeted ADCs <i>via</i> p38-Mediated Noncanonical Endocytosis in EGFR-Mutant Lung Cancer Cells

Antibody-drug conjugates (ADCs) have revolutionized targeted cancer therapy, with human epidermal growth factor receptor 2-targeted ADCs demonstrating notable clinical success. In contrast, the clinical efficacy of epidermal growth factor receptor (EGFR)-targeted ADCs has not yet been clearly demonstrated, owing to several underlying factors. In this study, we focused on one of the key determinants most directly linked to therapeutic efficacy, the intracellular uptake of ADCs, and examined the noncanonical endocytic pathway driven by p38-dependent phosphorylation of EGFR in PC-9 non-small cell lung cancer (NSCLC) cells harboring an EGFR exon 19 deletion. Using tumor necrosis factor-α to activate this pathway, we observed enhanced internalization of cetuximab-monomethyl auristatin E and increased cytotoxicity in vitro. Notably, we also found that cisplatin, the backbone of lung cancer chemotherapy, induces a similar noncanonical endocytic response, further supporting the physiological relevance of this pathway. Collectively, our results highlight noncanonical endocytosis as a tractable mechanism to enhance the intracellular delivery and antitumor activity of EGFR-targeted ADCs. This mechanistic insight provides a foundation for developing improved platforms and combination regimens capable of overcoming resistance in NSCLC.