Fig. 9: Long-Term EGFR TKI Treatment Induces deNG-IL6 to Drive Resistance.

In non-small cell lung cancer (NSCLC) cells, autocrine IL6 (NG-IL6) predominantly exhibits N-glycosylation at residue N73 and O-glycosylation at residue T170 in an EGFR TKI-naïve environment. NG-IL6 predominantly activates the canonical JAK-STAT3 axis, promoting cell proliferation. However, long-term treatment with EGFR TKIs leads to increased secretion of IL6 while concurrently suppressing the expression of N-glycosyltransferase complex components, primarily STT3A or STT3B, RPN1/2, DAD1, and DDOST. This suppression results in diminished N-glycosylation at N73 of NG-IL6, which subsequently reduces N-glycosylation at N73 of NG-IL6. Consequently, the proportion of NG-IL6 decreases, while the proportion of deNG-IL6 increases upon the acquisition of resistance. deNG-IL6, in turn, shifts signaling preference from the JAK-STAT3 axis to the SRC-YAP-SOX2 axis. The alternatively activated SRC-YAP-SOX2 signaling facilitates cellular plasticity and contributes to the development of drug resistance.