https://scholars.lib.ntu.edu.tw/handle/123456789/473727
標題: | Acquired resistance to EGFR tyrosine kinase inhibitors is mediated by the reactivation of STC2/JUN/AXL signaling in lung cancer | 作者: | Liu Y.-N. Tsai M.-F. SHANG-GIN WU Chang T.-H. TZU-HSIU TSAI Gow C.-H. YIH-LEONG CHANG JIN-YUAN SHIH |
公開日期: | 2019 | 出版社: | Wiley-Liss Inc. | 卷: | 145 | 期: | 6 | 起(迄)頁: | 1609-1624 | 來源出版物: | International Journal of Cancer | 摘要: | Constitutive activation of the epidermal growth factor receptor (EGFR) signaling pathway is implicated in the initiation and progression of lung cancer. EGFR tyrosine kinase inhibitor (TKI)-targeted therapy has become the standard treatment for nonsmall cell lung cancer (NSCLC) patients. However, acquired resistance to these agents remains a major obstacle for managing NSCLC. Here, we investigated a novel strategy to overcome EGFR TKI resistance by targeting the stanniocalcin 2 (STC2)-JUN-AXL pathway. We revealed that STC2 was expressed at significantly higher levels in EGFR TKI-resistant cells. Further, clinical analysis showed that STC2 expression was increased after the development of EGFR TKI resistance and that higher levels were correlated with shorter progression-free survival in EGFR TKI-treated lung cancer patients. Moreover, STC2 overexpression in EGFR TKI-sensitive cells resulted in EGFR TKI resistance. Conversely, genetic silencing of STC2 rendered EGFR TKI-resistant cells more sensitive to EGFR TKIs. Mechanically, STC2 enhanced AXL promoter activity by increasing the phosphorylation of c-Jun, which is an indispensable transcription factor that transactivates AXL. STC2 promoted activation of the JUN-AXL-extracellular signal-regulated kinase (ERK) signaling axis in lung cancer cells. Pharmacological or genetic inhibition of AXL-ERK activity inhibited STC2-mediated EGFR TKI resistance. We also demonstrated that PE2988 cells, a C797S-independent osimertinib-resistant primary cancer cell line from a lung cancer patient, responded to combined AXL inhibitor and osimertinib treatment. In conclusion, our research indicates that STC2 overexpression is important for acquired resistance to EGFR TKIs and that STC2-JUN-AXL-ERK signaling might be a potential therapeutic target to overcome resistance to EGFR TKIs. ? 2019 UICC |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85068127829&doi=10.1002%2fijc.32487&partnerID=40&md5=176b5c2ac5eec6a38c758e0a61e503e4 https://scholars.lib.ntu.edu.tw/handle/123456789/473727 |
ISSN: | 0020-7136 | DOI: | 10.1002/ijc.32487 | SDG/關鍵字: | epidermal growth factor receptor kinase inhibitor; gefitinib; hypocalcin; mitogen activated protein kinase; osimertinib; protein Axl; protein c jun; protein stanniocalcin 2; protein tyrosine kinase; transcription factor; unclassified drug; axl receptor tyrosine kinase; EGFR protein, human; enzyme inhibitor; epidermal growth factor receptor; glycoprotein; oncoprotein; protein c jun; protein tyrosine kinase; signal peptide; STC2 protein, human; animal cell; animal experiment; animal model; animal tissue; Article; carcinogenesis; controlled study; correlational study; drug resistance; drug response; drug sensitivity; enzyme activation; enzyme activity; enzyme inhibition; enzyme reactivation; gene silencing; human; human cell; human tissue; lung cancer; lung cancer cell line; male; molecularly targeted therapy; mouse; nonhuman; PE2988 cell line; priority journal; progression free survival; promoter region; protein expression; protein phosphorylation; signal transduction; adenocarcinoma; animal; Bagg albino mouse; disease free survival; drug effect; drug resistance; lung tumor; metabolism; nude mouse; pathology; phosphorylation; signal transduction; tumor cell line; xenograft; Adenocarcinoma; Animals; Cell Line, Tumor; Disease-Free Survival; Drug Resistance, Neoplasm; Enzyme Inhibitors; ErbB Receptors; Glycoproteins; Heterografts; Humans; Intercellular Signaling Peptides and Proteins; Lung Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-jun; Receptor Protein-Tyrosine Kinases; Signal Transduction |
顯示於: | 病理學科所 |
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