Research Papers:

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

Makoto Sudo _, Seiichi Mori, Vikas Madan, Henry Yang, Geraldine Leong and H. Phillip Koeffler

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2015; 6:814-824. https://doi.org/10.18632/oncotarget.2891

Metrics: PDF 1919 views  |   HTML 2294 views  |   ?  


Makoto Sudo1, Seiichi Mori2, Vikas Madan1, Henry Yang1, Geraldine Leong1 and H. Phillip Koeffler1,3,4

1 Cancer Science Institute of Singapore, NUS, Singapore

2 Division of Cancer Genomics, The Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan

3 Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

4 National University Cancer Institute, National University Hospital, Singapore


Makoto Sudo, email:

Keywords: combination chemotherapy, dasatinib, gefitinib, PRKCSH, short-hairpin RNA library screening, thioridazine

Received: August 19, 2014 Accepted: November 24, 2014 Published: November 25, 2014


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.

Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 2891