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Y.J. Cho

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-002 - Reversal of Resistance to EGFR tyrosine kinase inhibitor by EGFR T790M specific siRNA in Non-Small Cell Lung Cancer (ID 1141)

      09:30 - 16:30  |  Author(s): Y.J. Cho

      • Abstract

      Analysis for EGFR mutation became new standard in management of lung adenocarcinoma. Mutations in EGFR tyrosine kinase domain such as L858R or small deletions in exon 19 result in sustained phosphorylation of EGFR and become driver oncogenic mutation. EGFR TKI, such as gefitinib, induces dramatic response in lung adenocarcinoma with sensitive mutations. Unfortunately, this dramatic response can not last long and resistance to EGFR TKI emerges and induces treatment failure. More than 50% of resistant mutations are EGFR T790M mutation. In this study, we investigated the role of siRNA specific to EGFR T790M and its clinical significance.

      We designed three sequences (siRNA1, 2, 3) specific to EGFR T790M according to siRNA design guideline. Lung cancer cells were used: A549, NCI H460 (EGFR; wild type), NCI H1975 (EGFR L858R + T790M), PC9 (EGFR small deletion in exon 19), PC9-G (EGFR small deletion in exon 19 + T790M). We investigated the effect of three siRNAs on suppression of EGFR T790M and reversal of resistance to gefitinib.

      Transfection of siRNA 1 and 3 showed marked suppression of EGFR expression in NCI H1975 and PC9-G, however, siRNA 2 failed to suppress. All siRNA don't affect EGFR expression in A549, NCI H460 and PC-9. This finding suggested that suppressions of EGFR by siRNA 1 and 3 were specific to EGFR T790M. EGFR T790M siRNA 1 and 3 not 2, markedly suppressed the growth of NCI H1975 and PC9-G via increased apoptotic cell death and also suppressed in vitro tumorigenicity. No significant effect was found in other cell lines. This finding strongly supports that EGFR T790M is another oncogenic driver mutation. Cotreatment of EGFR siRNA 1 and 3 with gefitinib induced marked increase in sensitivity of NCI H1975 and PC-9 to gefitinib (synergistic interaction), however, no effects were found in A549 and NCI H460.

      Application of EGFR T790M specific siRNA can reverse the resistance of lung adenocarcinoma and shows its potential to be a breakthrough in EGFR TKI. Further study will focus on preclinical application with efficient delivery system, such as, nanotechnology or viral vectors. (This study was supported by a grant from the National Research Foundation of Korea, 2011-0002169).