title: Short-hairpin RNA library: identification of therapeutic partners for gefitinib-resistant non-small cell lung cancer.
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-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.
authors.affiliation: Cancer Science Institute of Singapore, NUS, Singapore.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sudo
authors.affiliation: Division of Cancer Genomics, The Cancer Institute of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mori
authors.affiliation: Cancer Science Institute of Singapore, NUS, Singapore.
authors.forename: Vikas
authors.initials: V
authors.lastname: Madan
authors.affiliation: Cancer Science Institute of Singapore, NUS, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Cancer Science Institute of Singapore, NUS, Singapore.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Leong
authors.affiliation: Cancer Science Institute of Singapore, NUS, Singapore.Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.National University Cancer Institute, National University Hospital, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D011799:Quinazolines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D034741:RNA, Small Interfering; D000077156:Gefitinib