Cited 2 time in webofscience Cited 2 time in scopus

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

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
Authors
Kim, N[Kim, Nayoung]Cho, A[Cho, Ahye]Watanabe, H[Watanabe, Hideo]Choi, YL[Choi, Yoon-La]Aziz, M[Aziz, Meraj]Kassner, M[Kassner, Michelle]Joung, JG[Joung, Je-Gun]Park, AKJ[Park, Angela K. J.]Francis, JM[Francis, Joshua M.]Bae, JS[Bae, Joon Seol]Ahn, SM[Ahn, Soo-min]Kim, KM[Kim, Kyoung-Mee]Park, JO[Park, Joon Oh]Park, WY[Park, Woong-Yang]Ahn, MJ[Ahn, Myung-Ju]Park, K[Park, Keunchil]Koo, J[Koo, Jaehyung]Yin, HH[Yin, Hongwei Holly]Cho, J[Cho, Jeonghee]
DGIST Authors
Koo, J[Koo, Jaehyung]
Issue Date
2016-03-22
Citation
Oncotarget, 7(12), 13797-13809
Type
Article
Article Type
Article
Keywords
Animal ExperimentAnimal ModelCancer ResistanceControlled StudyEGFREpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor GeneErlotinibErlotinib ResistanceGeneGene ExpressionGene MutationGenetic AssociationGenome AnalysisHumanHuman TissueImmunohistochemistryIn Vitro StudyIn Vivo StudyLung AdenocarcinomaMaleMouseNon-HumanPhosphatidylinositol 3 KinaseProtein Kinase BRNA SequenceSCRN1SCRN1 GeneSignal TransductionUpregulation
ISSN
1949-2553
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.
URI
http://hdl.handle.net/20.500.11750/2707
DOI
10.18632/oncotarget.7318
Publisher
Impact Journals LLC
Related Researcher
  • Author Koo, Jae Hyung The Koo Lab - ChemoReception Laboratory(CRLab)
  • Research Interests
Files:
There are no files associated with this item.
Collection:
New BiologyETC1. Journal Articles


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