Cited 2 time in
Cited 2 time in
Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation
- Integrated genomic approaches identify upregulation of SCRN1 as a novel mechanism associated with acquired resistance to erlotinib in PC9 cells harboring oncogenic EGFR mutation
- 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
- Oncotarget, 7(12), 13797-13809
- Article Type
- Animal Experiment; Animal Model; Cancer Resistance; Controlled Study; EGFR; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Gene; Erlotinib; Erlotinib Resistance; Gene; Gene Expression; Gene Mutation; Genetic Association; Genome Analysis; Human; Human Tissue; Immunohistochemistry; In Vitro Study; In Vivo Study; Lung Adenocarcinoma; Male; Mouse; Non-Human; Phosphatidylinositol 3 Kinase; Protein Kinase B; RNA Sequence; SCRN1; SCRN1 Gene; Signal Transduction; Upregulation
- 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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- Brain and Cognitive SciencesThe Koo Lab - ChemoReception Laboratory(CRLab)1. Journal Articles
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