Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2016-05, Vol.113 (18), p.E2526-E2535

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2016

Quelle

Elektronische Zeitschriftenbibliothek - Freely accessible e-journals

Beschreibungen/Notizen

• 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-κB, 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-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.