NF-κB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance.
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.
National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan;
Ching-Feng
CF
Chiu
National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan;
Yi-Wen
YW
Chang
Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan;
Kuang-Tai
KT
Kuo
Department of Biotechnology, Asia University, Taichung City 413, Taiwan;
Yu-Shiuan
YS
Shen
School of Medicine, Chang Gung University, Taoyuan City 33305, Taiwan; Division of Pulmonary Oncology and Interventional Bronchoscopy, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan City 33305, Taiwan;
Chien-Ying
CY
Liu
Divisions of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung City 404, Taiwan; School of Medicine, China Medical University, Taichung City 404, Taiwan;
Yang-Hao
YH
Yu
National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan;
Ching-Chia
CC
Cheng
Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan;
Kang-Yun
KY
Lee
Institute of Population Health Sciences, National Health Research Institutes, Miaoli County 35053, Taiwan;
Feng-Chi
FC
Chen
Department of Biological Science and Technology, National Chiao Tung University, Hsinchu City 300, Taiwan;
Min-Kung
MK
Hsu
Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei City 10617, Taiwan;
Tsang-Chih
TC
Kuo
National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan;
Jui-Ti
JT
Ma
National Institute of Cancer Research, National Health Research Institutes, Miaoli County 35053, Taiwan; Department of Biotechnology, Asia University, Taichung City 413, Taiwan; Graduate Institute of Cancer Biology, China Medical University, Taichung City 404, Taiwan; Center for Molecular Medicine, China Medical University Hospital, Taichung City 404, Taiwan jlsu@nhri.org.tw.
Jen-Liang
JL
Su
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
EGFR; NF-κB; gefitinib; lung cancer; miR-155