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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-05, Vol.113 (18), p.E2526-E2535
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Biological Sciences; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Drug Resistance, Neoplasm; Female; Forkhead Box Protein O3 - metabolism; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Middle Aged; Mutation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; NF-kappa B - metabolism; PNAS Plus; Protein Kinase Inhibitors - administration & dosage; Quinazolines - administration & dosage; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Treatment Outcome; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1522612113

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.