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 K.J. 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, Jeonghee Cho

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Pages (from-to)13797-13809
Number of pages13
JournalOncotarget
Volume7
Issue number12
DOIs
StatePublished - 22 Mar 2016

Keywords

  • EGFR
  • Erlotinib resistance
  • Lung adenocarcinoma
  • SCRN1

Fingerprint

Dive into the research topics of 'Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation'. Together they form a unique fingerprint.

Cite this