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https://doi.org/10.18632/oncotarget.2891
Title: | Short-hairpin RNA library: Identification of therapeutic partners for gefitinib-resistant non-small cell lung cancer | Authors: | Sudo M. Mori S. Madan V. Yang H. Leong G. Koeffler H.P. |
Keywords: | 1 (5 isoquinolinesulfonyl) 2 methylpiperazine ampicillin bromocriptine camptothecin CD27 antigen clotrimazole dasatinib econazole fenoterol fluindostatin gefitinib hexamethonium bromide ifenprodil methylprednisolone metolazone nabumetone procaine protein kinase B rottlerin roxithromycin short hairpin RNA thioridazine thiostrepton tolfenamic acid vanoxerine antineoplastic agent gefitinib quinazoline derivative small interfering RNA apoptosis Article cancer inhibition cell death computer model controlled study drug potentiation drug resistance drug screening drug sensitivity gene gene silencing human human cell lung cancer cell line molecular library non small cell lung cancer PRKCSH gene RNA interference signal transduction Carcinoma, Non-Small-Cell Lung cell proliferation genetics Lung Neoplasms tumor cell line Antineoplastic Agents Apoptosis Carcinoma, Non-Small-Cell Lung Cell Line, Tumor Cell Proliferation Drug Resistance, Neoplasm Humans Lung Neoplasms Quinazolines RNA, Small Interfering Signal Transduction |
Issue Date: | 2015 | Publisher: | Impact Journals LLC | Citation: | Sudo M., Mori S., Madan V., Yang H., Leong G., Koeffler H.P. (2015). Short-hairpin RNA library: Identification of therapeutic partners for gefitinib-resistant non-small cell lung cancer. Oncotarget 6 (2) : 814-824. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.2891 | Abstract: | Somatic mutations of the epidermal growth factor receptor often cause resistance to therapy with tyrosine kinase inhibitor in non-small cell lung cancer (NSCLC). In this study, we aimed to identify partner drugs and pathways that can induce cell death in combination with gefitinib in NSCLC cells. We undertook a genome-wide RNAi screen to identify synthetic lethality with gefitinib in tyrosine kinase inhibitor resistant cells. The screening data were utilized in different approaches. Firstly, we identified PRKCSH as a candidate gene, silencing of which induces apoptosis of NSCLC cells treated with gefitinib. Next, in an in silico gene signature pathway analysis of shRNA library data, a strong correlation of genes involved in the CD27 signaling cascade was observed. We showed that the combination of dasatinib (NF-?B pathway inhibitor) with gefitinib synergistically inhibited the growth of NSCLC cells. Lastly, utilizing the Connectivity Map, thioridazine was identified as a top pharmaceutical perturbagen. In our experiments, it synergized with gefitinib to reduce p-Akt levels and to induce apoptosis in NSCLC cells. Taken together, a pooled short-hairpin library screen identified several potential pathways and drugs that can be therapeutic targets for gefitinib resistant NSCLC. | Source Title: | Oncotarget | URI: | https://scholarbank.nus.edu.sg/handle/10635/175535 | ISSN: | 19492553 | DOI: | 10.18632/oncotarget.2891 |
Appears in Collections: | Staff Publications Elements |
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