NF-κB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance

Ching Feng Chiu, Yi Wen Chang, Kuang Tai Kuo, Yu Shiuan Shen, Chien Ying Liu, Yang Hao Yu, Ching Chia Cheng, Kang Yun Lee, Feng Chi Chen, Min Kung Hsu, Tsang Chih Ku, Jui Ti Ma, Jen Liang Su*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

72 Scopus citations


Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3'UTR of FOXO3a and was transcriptionally regulated by NF-?B, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF- ?B/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

Original languageEnglish
Pages (from-to)E2526-E2535
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number18
StatePublished - 03 05 2016
Externally publishedYes


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