Blocking the PI3K/AKT and MEK/ERK signaling pathways can overcome gefitinib-resistance in non-small cell lung cancer cell lines

H Li, G Schmid-Bindert, D Wang, Y Zhao, X Yang, B Su, C Zhou
Advances in Medical Sciences 2011, 56 (2): 275-84

PURPOSE: To investigate the effects of gefitinib (EGFR-TKI), LY294002 (PI3K inhibitor) and U0126 (MEK inhibitor) on proliferation and apoptosis in five non-small cell lung cancer (NSCLC) cell lines (PC9, PC9/AB2, H1975, H1299 and A549).

METHODS: The inhibitory rates of cells were tested by MTT and apoptosis was detected through flow cytometry when treated with gefitinib, LY294002 and U0126.

RESULTS: The sensitivity to gefitinib was different in different cell lines, which was associated with EGFR mutation type. The cells with EGFR mutation were more sensitive than those with EGFR wild-type, except PC9/AB2 cells. LY294002 and U0126 can inhibit cell proliferation and promote apoptosis in all five cell lines. The sensitivity to gefitinib was restored partially in the resistant cell lines by combining gefitinib with LY294002 or U0126. The effects on cell proliferation and apoptosis were stronger in cells with EGFR mutation when PI3K/AKT pathway was blocked, however, for cells with EGFR wild-type, the effects were stronger when the MEK pathway was blocked. When the PI3K and MEK pathways were blocked together, proliferation inhibition and apoptosis level in NSCLC cells was similar to that in cells treated with EGFR TKI. There were some differences according to EGFR mutation type, suggesting that EGFR mutations may result in alterations of downstream signaling pathways.

CONCLUSION: The sensitivity of gefitinib resistant cell lines can be restored partially when the two downstream signaling pathways are blocked. However, these cells were still drug resistant, suggesting that the activation of PI3K and MEK pathways is not the only mechanism of EGFR-resistance.

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