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Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer
- Title
- Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer
- 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
- Ewha Authors
- 김완규; 이해승
- SCOPUS Author ID
- 김완규
- Issue Date
- 2018
- Journal Title
- MOLECULAR CANCER
- ISSN
- 1476-4598
- Citation
- MOLECULAR CANCER vol. 17
- Keywords
- Chemoresistance; Mesenchymal cancer; Pharmacogenomics; Drug repurposing; Biomarker; ITGB3; NF-B; Atorvastatin; Systems pharmacology
- Publisher
- BMC
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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-B 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.
- DOI
- 10.1186/s12943-018-0924-8
- Appears in Collections:
- 자연과학대학 > 생명과학전공 > Journal papers
- Files in This Item:
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