Oncotarget

Research Papers:

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

Nayoung Kim, Ahye Cho, Hideo Watanabe, Yoon-La Choi, Meraj Aziz, Michelle Kassner, Je-Gun Joung, Angela Kyung-Joo Park, Joshua M. Francis, Joon Seol Bae, Soo-min Ahn, Kyoung-Mee Kim, Joon Oh Park, Woong-Yang Park, Myung-Ju Ahn, Keunchil Park, Jaehyung Koo, Hongwei Holly Yin and Jeonghee Cho _

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Oncotarget. 2016; 7:13797-13809. https://doi.org/10.18632/oncotarget.7318

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Abstract

Nayoung Kim1,2, Ahye Cho2, Hideo Watanabe3,4, Yoon-La Choi2,5, Meraj Aziz6, Michelle Kassner6, Je-Gun Joung7, Angela Kyung-Joo Park1,2, Joshua M. Francis8, Joon Seol Bae7, Soo-min Ahn5, Kyoung-Mee Kim5, Joon Oh Park9, Woong-Yang Park2,7, Myung-Ju Ahn9, Keunchil Park9, Jaehyung Koo10, Hongwei Holly Yin6, Jeonghee Cho1,2,7

1Department of NanoBio Medical Science, Dankook University, Cheonan 31116, Republic of Korea

2Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 135-967, Republic of Korea

3Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York, NY 10029, USA

4Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

5Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea

6Cancer and Cell Biology Division, Translational Genomics Research Institute, Scottsdale, AZ 85259, USA

7Samsung Genome Institute, Samsung Medical Center, Seoul 135-967, Republic of Korea

8Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA

9Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-967, Republic of Korea

10Department 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.


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