Tyrosine kinase inhibitor-induced IL-6/STAT3 activation decreases sensitivity of EGFR-mutant non-small cell lung cancer to icotinib.

Tyrosine kinase Inhibitors (TKIs) of epidermal growth factor receptor (EGFR) has considerably benefited for non-small cell lung carcinomas (NSCLC) harbor mutations in EGFR. However, the factors attenuating EGFR-TKI efficiency are obstacles to inhibit the proliferation of EGFR-mutant NSCLC cells successfully. Clarifying the insensitivity mechanisms of EGFR-TKI would help to develop new treatment strategy. In this study, the sensitivity of EGFR-mutant NSCLC cell lines, PC9 and HCC827, to icotinib was detected. Similar with other EGFR-TKIs such as gefitinib and erlortinib in previous research, the proliferation of two cell lines was apparently inhibited. However, we surprisingly found that contrast with the suppression of EGFR-AKT/ERK pathway, STAT3 was significantly activated in PC9 cells with the treatment of icotinib, but not in HCC827 cells. Further study confirmed that icotinib concomitantly induced IL-6 secretion and src activation in PC9 cells. Moreover, with the treatment of IL-6 neutralizing antibody or src inhibitor, dasatinib, icotinib-induced phosphorylation of STAT3 was reduced, as well as the sensitivity of PC9 to icotinib was also partially increased. Our results suggest that Src/IL-6/STAT3 bypass pathway is activated to maintain cell survival when the EGFR pathway was inhibited by TKIs, even in some EGFR-mutant NSCLC cells sensitive to TKIs. This finding provides a groundwork for potential combinatorial treatment with TKIs and Src or STAT3 inhibitor to improve icotinib sensitivity.