title: Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation.
abstract: Therapies targeting the tyrosine kinase activity of Epidermal Growth Factor Receptor (EGFR) have been proven to be effective in treating a subset of non-small cell lung cancer (NSCLC) patients harboring activating EGFR mutations. Inevitably these patients develop resistance to the EGFR-targeted tyrosine kinase inhibitors (TKIs). Here, we performed integrated genomic analyses using an in vitro system to uncover alternative genomic mechanisms responsible for acquired resistance to EGFR-TKIs. Specifically, we identified 80 genes whose expression is significantly increased in the erlotinib-resistant clones. RNAi-based systematic synthetic lethal screening of these candidate genes revealed that suppression of one upregulated transcript, SCRN1, a secernin family member, restores sensitivity to erlotinib by enhancing inhibition of PI3K/AKT signaling pathway. Furthermore, immunohistochemical analysis revealed increased levels of SCRN1 in 5 of 11 lung tumor specimens from EGFR-TKIs resistant patients. Taken together, we propose that upregulation of SCRN1 is an additional mechanism associated with acquired resistance to EGFR-TKIs and that its suppression serves as a novel therapeutic strategy to overcome drug resistance in these patients.
authors.affiliation: Department of NanoBio Medical Science, Dankook University, Cheonan 31116, Republic of Korea.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 135-967, Republic of Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 135-967, Republic of Korea.
authors.forename: Ahye
authors.initials: A
authors.lastname: Cho
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York, NY 10029, USA.|Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Hideo
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 135-967, Republic of Korea.|Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea.
authors.forename: Yoon-La
authors.initials: YL
authors.lastname: Choi
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
authors.forename: Meraj
authors.initials: M
authors.lastname: Aziz
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kassner
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul 135-967, Republic of Korea.
authors.forename: Je-Gun
authors.initials: JG
authors.lastname: Joung
authors.affiliation: Department of NanoBio Medical Science, Dankook University, Cheonan 31116, Republic of Korea.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 135-967, Republic of Korea.
authors.forename: Angela Kyung-Joo
authors.initials: AK
authors.lastname: Park
authors.affiliation: Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Francis
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul 135-967, Republic of Korea.
authors.forename: Joon Seol
authors.initials: JS
authors.lastname: Bae
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea.
authors.forename: Soo-Min
authors.initials: SM
authors.lastname: Ahn
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea.
authors.forename: Kyoung-Mee
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 135-967, Republic of Korea.|Samsung Genome Institute, Samsung Medical Center, Seoul 135-967, Republic of Korea.
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Brain and Cognitive Sciences, DGIST, Daegu 42988, Republic of Korea.
authors.forename: Jaehyung
authors.initials: J
authors.lastname: Koo
authors.affiliation: Cancer and Cell Biology Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA.
authors.forename: Hongwei Holly
authors.initials: HH
authors.lastname: Yin
authors.affiliation: Department of NanoBio Medical Science, Dankook University, Cheonan 31116, Republic of Korea.|Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 135-967, Republic of Korea.|Samsung Genome Institute, Samsung Medical Center, Seoul 135-967, Republic of Korea.
authors.forename: Jeonghee
authors.initials: J
authors.lastname: Cho
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D023281:Genomics / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C471696:SCRN1 protein, human; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; SCRN1; erlotinib resistance; lung adenocarcinoma