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Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer

Cited 17 time in Web of Science Cited 16 time in Scopus
Authors
Hong, Soon-Ki; Lee, Haeseung; Kwon, Ok-Seon; Song, Na-Young; Lee, Hyo-Ju; Kang, Seungmin; Kim, Jeong-Hwan; Kim, Mirang; Kim, Wankyu; Cha, Hyuk-Jin
Issue Date
2018-12-18
Publisher
BioMed Central
Citation
Molecular Cancer, 17(1):175
Keywords
ChemoresistanceMesenchymal cancerPharmacogenomicsDrug repurposingBiomarkerITGB3NF-κBAtorvastatinSystems pharmacology
Abstract
Even when targets responsible for chemoresistance are identified, drug development is often hampered due to the poor druggability of these proteins. We systematically analyzed therapy-resistance with a large-scale cancer cell transcriptome and drug-response datasets and predicted the candidate drugs based on the gene expression profile. Our results implicated the epithelial–mesenchymal transition as a common mechanism underlying resistance to chemotherapeutic drugs. Notably, we identified ITGB3, whose expression was abundant in both drug resistance and mesenchymal status, as a promising target to overcome chemoresistance. We also confirmed that depletion of ITGB3 sensitized cancer cells to conventional chemotherapeutic drugs by modulating the NF-κB signaling pathway. Considering the poor druggability of ITGB3 and the lack of feasible drugs to directly inhibit this protein, we took an in silico screening for drugs mimicking the transcriptome-level changes caused by knockdown of ITGB3. This approach successfully identified atorvastatin as a novel candidate for drug repurposing, paving an alternative path to drug screening that is applicable to undruggable targets.
ISSN
1476-4598
Language
English
URI
https://hdl.handle.net/10371/147069
DOI
https://doi.org/10.1186/s12943-018-0924-8
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Journal Papers (저널논문_약학과)
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