Please use this identifier to cite or link to this item: 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
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