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Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer
Cited 24 time in
Web of Science
Cited 24 time in Scopus
- Authors
- Issue Date
- 2018-12-18
- Publisher
- BioMed Central
- Citation
- Molecular Cancer, 17(1):175
- Keywords
- Chemoresistance ; Mesenchymal cancer ; Pharmacogenomics ; Drug repurposing ; Biomarker ; ITGB3 ; NF-κB ; Atorvastatin ; Systems 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
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