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

Mol Cancer. 2018 Dec 18;17(1):175. doi: 10.1186/s12943-018-0924-8.


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.

Keywords: Atorvastatin; Biomarker; Chemoresistance; Drug repurposing; ITGB3; Mesenchymal cancer; NF-κB; Pharmacogenomics; Systems pharmacology.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Cell Line, Tumor
  • Drug Discovery / methods
  • Drug Resistance, Neoplasm / genetics*
  • Epithelial-Mesenchymal Transition / genetics*
  • Humans
  • Integrin beta3 / genetics*
  • Lung Neoplasms / genetics*
  • NF-kappa B / genetics
  • Pharmacogenetics / methods
  • Signal Transduction / genetics


  • ITGB3 protein, human
  • Integrin beta3
  • NF-kappa B