title: siRNA delivered by EGFR-specific scFv sensitizes EGFR-TKI-resistant human lung cancer cells.
abstract: The overexpression of epidermal growth factor receptor (EGFR) is closely associated with a poor outcome in non-small cell lung cancer (NSCLC), and EGFR is an ideal biomarker for the targeted therapy of NSCLC. Although patients with EGFR-activating mutations respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), they eventually acquire resistance, which typically results from a secondary EGFR mutation or the activation of other signaling pathways. Novel approaches to overcome or prevent EGFR-TKI resistance are clinically important. In this study, we developed an EGFR-scFv-arginine nonamer peptide fusion protein, s-9R, as an siRNA carrier. Here, we show that s-9R effectively and specifically delivers EGFR-siRNAs, KRAS-siRNA and MET-siRNA into NSCLC cells and silences the expression of target genes. The sensitivity of NSCLC cells to gefitinib was restored after treatment with the s-9R/siRNA complex, and the apoptosis rates of the treated cells were significantly higher than those of the control groups. Furthermore, the co-administration of s-9R/siRNA and gefitinib successfully suppressed the progression of H1975 xenograft tumors and extended the life span of tumor-bearing nude mice. Collectively, the results of this study provide not only a new scFv derivative for delivering siRNA into EGFR-overexpressing, TKI-resistant NSCLC cells but also a novel method for overcoming TKI resistance.
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China; Department of Geriatrics, The Central Hospital of Xianyang, 78 Renming East Road, Xianyang 712000, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Fakai
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Ye
authors.affiliation: The Organ Transplant Institute, The Fuzhou General Hospital (DongFang Hospital), Xiamen University, 156 West Ring Road, Fuzhou 350025, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, Naval General Hospital, 6 Fucheng Road, Beijing 100048, China.
authors.forename: Mi
authors.initials: M
authors.lastname: Zhang
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
authors.forename: Angang
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Respiratory Medicine, Naval General Hospital, 6 Fucheng Road, Beijing 100048, China. Electronic address: fenghs99@163.com.
authors.forename: Huasong
authors.initials: H
authors.lastname: Feng
authors.affiliation: The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China. Electronic address: ruizhang@fmmu.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China. Electronic address: majrenxl@fmmu.edu.cn.
authors.forename: Xinling
authors.initials: X
authors.lastname: Ren
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D057127:Single-Chain Antibodies / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D057127:Single-Chain Antibodies; D066246:ErbB Receptors
keywords: NSCLC; RNA interference; Resistance; Targeted therapy; Tyrosine kinase inhibitors (TKIs); scFv