https://scholars.lib.ntu.edu.tw/handle/123456789/523546
Title: | Overcoming EGFR T790M-based tyrosine kinase inhibitor resistance with an allele-specific DNAzyme | Authors: | Lai W.-Y. Chen C.-Y. Yang S.-C. Wu J.-Y. Chang C.-J. PAN-CHYR YANG Peck K. |
Keywords: | DNAzyme; EGFR T790M; NSCLC; TKI | Issue Date: | 2014 | Publisher: | Nature Publishing Group | Journal Volume: | 3 | Start page/Pages: | e150 | Source: | Molecular Therapy - Nucleic Acids | Abstract: | Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the main therapeutic agents used to treat non-small-cell lung cancer patients harboring EGFR-activating mutations. However, most of these patients will eventually develop resistance, 50% of which are due to a secondary mutation at T790M in the EGFR. In this paper, we describe the development of an allele-specific DNAzyme, DzT, that can specifically silence EGFR T790M mutant messenger RNA while leaving wild-type EGFR intact. Allele-specific silencing of EGFR T790M expression and downstream signaling by DzT triggered apoptosis in non-small-cell lung cancer cells harboring this mutant. Adding a cholesterol-triethylene glycol group on the 3′-end of DzT (cDzT) improved drug efficacy, increasing inhibitory effect on cell viability from 46 to 79% in T790M/L858R-harboring H1975TM/LR non-small-cell lung cancer cells, without loss of allele specificity. Combined treatment with cDzT and BIBW-2992, a second-generation EGFR-tyrosine kinase inhibitor, synergistically inhibited EGFR downstream signaling and suppressed the growth of xenograft tumors derived from H1975TM/LR cells. Collectively, these results indicate that the allele-specific DNAzyme, DzT, may provide an alternative treatment for non-small-cell lung cancer that is capable of overcoming EGFR T790M mutantbased tyrosine kinase inhibitor resistance. ? 2014 The American Society of Gene & Cell Therapy All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84925269097&doi=10.1038%2fmtna.2014.3&partnerID=40&md5=8d9702b1d6da322feeb0f299ffb86c1d https://scholars.lib.ntu.edu.tw/handle/123456789/523546 |
ISSN: | 2162-2531 | DOI: | 10.1038/mtna.2014.3 | SDG/Keyword: | afatinib; caspase 3; cholesterol; deoxyribozyme; epidermal growth factor receptor; gefitinib; genomic DNA; messenger RNA; mitogen activated protein kinase; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein kinase B; STAT3 protein; triethylene glycol; allele; animal cell; animal experiment; animal model; apoptosis; Article; cancer chemotherapy; cancer gene therapy; cancer inhibition; cancer resistance; cancer survival; cell activation; cell count; cell killing; cell mutant; cell proliferation; cell survival; cell viability; controlled study; dimerization; DNA sequence; drug efficacy; drug potentiation; drug structure; endosome; enzyme phosphorylation; experimental neoplasm; flow cytometry; gene expression; gene silencing; genetic transfection; human; immunoblotting; lung cancer cell line; mouse; non small cell lung cancer; nonhuman; point mutation; priority journal; protein expression; quantitative analysis; reverse transcription polymerase chain reaction; signal transduction; tumor xenograft; wild type |
Appears in Collections: | 醫學系 |
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