Lai W.-Y.Chen C.-Y.Yang S.-C.Wu J.-Y.Chang C.-J.PAN-CHYR YANGPeck K.2020-12-022020-12-0220142162-2531https://www.scopus.com/inward/record.uri?eid=2-s2.0-84925269097&doi=10.1038%2fmtna.2014.3&partnerID=40&md5=8d9702b1d6da322feeb0f299ffb86c1dhttps://scholars.lib.ntu.edu.tw/handle/123456789/523546Epidermal 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.DNAzyme; EGFR T790M; NSCLC; TKI[SDGs]SDG3afatinib; 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 typejournal article10.1038/mtna.2014.32-s2.0-84925269097