Objective:To investigate relationship between connexin 43（Cx43）expression and non-small-cell lung cancer（NSCLC）cells with primary resistance to gefitinib. Methods:Gefitinib efficacy in A549

H1299 cells and Calu3 cells was detected by MTT assay. The protein expression of Cx43 and phospho-Akt（p-Akt）was detected by Western blot. The functional gap junction intercellular communication（GJIC）was measured by ‘parachute’assay. The cellular localization of Cx43 protein was evaluated by immunofluorescence staining. Results:MTT assay showed that gefitinib cytotoxicity in Calu3 cells is significantly more than that in A549 and H1299 cells with IC50 of（0.064 ±0.011） μmol/L versus（13.64 ±0.015） μmol/L and（20.054 ±0.012） μmol/L

indicating that A549 and H1299 cells were primary resistance to gefitinib. Expression of Cx43 in Calu3 cells was significantly lower than that in A549 and H1299 cells（P<0.01）. Moreover

p-Akt protein in Calu3 cells was obviously lower than that in A549 and H1299 cells（P<0.01）. Furthermore

functional GJIC was found in A549 and H1299 with or without RA（a well-defined GJIC enhancer）treatment

but not in Calu3 cells. Immunofluorescence staining clearly showed that Cx43 protein deferentially accumulates at the plasma membrane of A549 cells

the plasma membrane and cytoplasm of H1299 cells while the cytoplasm of Calu3 cells. Conclusion:Up-regulation of Cx43 at the plasma membrane and their derived GJIC in A549 and H1299 cells may contribute to the primary resistance to gefitinib by activation of PI3 K/Akt signaling pathway.