Work

Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation

Year: 2016

Type: article

Abstract: // Nayoung Kim 1, 2 , Ahye Cho 2 , Hideo Watanabe 3, 4 , Yoon-La Choi 2, 5 , Meraj Aziz 6 , Michelle Kassner 6 , Je-Gun Joung 7 , Angela Kyung-Joo Park 1, 2 , Joshua M. Francis 8 , Joon Seol Bae 7 , Soo-min Ahn 5 , Kyoung-Mee Kim 5 , Joon Oh Park 9 , Woong-Yang Park 2, 7 , Myung-Ju Ahn 9 , Keunchil Park 9 , Jaehyung Koo 10 , Hongwei Holly Yin 6 , Jeonghee Cho 1, 2, 7 1 Department of NanoBio Medical Science, Dankook University, Cheonan 31116, Republic of Korea 2 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 135-967, Republic of Korea 3 Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York, NY 10029, USA 4 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA 5 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea 6 Cancer and Cell Biology Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA 7 Samsung Genome Institute, Samsung Medical Center, Seoul 135-967, Republic of Korea 8 Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA 9 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea 10 Department of Brain and Cognitive Sciences, DGIST, Daegu 42988, Republic of Korea Correspondence to: Jeonghee Cho, e-mail: [email protected] Keywords: EGFR, SCRN1, lung adenocarcinoma, erlotinib resistance Received: July 24, 2015 Accepted: January 27, 2016 Published: February 11, 2016 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.7318