Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer
- 주제(키워드) Atorvastatin , Biomarker , Chemoresistance , Drug repurposing , ITGB3 , Mesenchymal cancer , NF-κB , Pharmacogenomics , Systems pharmacology
- 등재 SCIE, SCOPUS
- 발행기관 BioMed Central Ltd.
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000156372
- 본문언어 영어
- Published As http://dx.doi.org/10.1186/s12943-018-0924-8
초록/요약
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. © 2018 The Author(s).
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