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NF-?B-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance.


ABSTRACT: 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.

SUBMITTER: Chiu CF 

PROVIDER: S-EPMC4983816 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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

Chiu Ching-Feng CF   Chang Yi-Wen YW   Kuo Kuang-Tai KT   Shen Yu-Shiuan YS   Liu Chien-Ying CY   Yu Yang-Hao YH   Cheng Ching-Chia CC   Lee Kang-Yun KY   Chen Feng-Chi FC   Hsu Min-Kung MK   Kuo Tsang-Chih TC   Ma Jui-Ti JT   Su Jen-Liang JL  

Proceedings of the National Academy of Sciences of the United States of America 20160418 18


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  ...[more]

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