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

Soon Ki Hong, Haeseung Lee, Ok Seon Kwon, Na Young Song, Hyo Ju Lee, Seungmin Kang, Jeong Hwan Kim, Mirang Kim, Wankyu Kim, Hyuk Jin Cha

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish
Article number175
JournalMolecular Cancer
Volume17
Issue number1
DOIs
StatePublished - 18 Dec 2018

Keywords

  • Atorvastatin
  • Biomarker
  • Chemoresistance
  • Drug repurposing
  • ITGB3
  • Mesenchymal cancer
  • NF-κB
  • Pharmacogenomics
  • Systems pharmacology

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