Short-hairpin RNA library: identification of therapeutic partners for gefitinib-resistant non-small cell lung cancer

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...

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Bibliographic Details
Published in:Oncotarget 2015-01, Vol.6 (2), p.814-824
Main Authors: Sudo, Makoto, Mori, Seiichi, Madan, Vikas, Yang, Henry, Leong, Geraldine, Koeffler, H Phillip
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis - genetics
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - therapy
Cell Line, Tumor
Cell Proliferation - genetics
Drug Resistance, Neoplasm
Humans
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - therapy
Quinazolines - pharmacology
Research Paper
RNA, Small Interfering - genetics
RNA, Small Interfering - pharmacology
Signal Transduction
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Summary: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-κB 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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.2891