Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer
- 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
- BioMed Central
- Molecular Cancer, 17(1):175
- Chemoresistance; Mesenchymal cancer; Pharmacogenomics; Drug repurposing; Biomarker; ITGB3; NF-κB; Atorvastatin; Systems pharmacology
- 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.