Publication in refereed journal
香港中文大学研究人员 ( 现职)
| 莫树锦教授 (肿瘤学系) |
全文
| 数位物件识别号 (DOI) http://dx.doi.org/10.1172/JCI73048 |
引用次数
Web of Sciencehttp://aims.cuhk.edu.hk/converis/portal/Publication/24WOS source URL
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摘要The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC.
着者Park KS, Raffeld M, Moon YW, Xi LQ, Bianco C, Pham T, Lee LC, Mitsudomi T, Yatabe Y, Okamoto I, Subramaniam D, Mok T, Rosell R, Luo J, Salomon DS, Wang YS, Giaccone G
期刊名称Journal of Clinical Investigation
出版年份2014
月份7
日期1
卷号1http://aims.cuhk.edu.hk/converis/portal/Publication/24
期次7
出版社American Society for Clinical Investigation
页次3003 - 3015
国际标準期刊号0021-9738
电子国际标準期刊号1558-8238
语言英式英语
Web of Science 学科类别Medicine, Research & Experimental; MEDICINE, RESEARCH & EXPERIMENTAL; Research & Experimental Medicine
