Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer
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 candid...
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doaj-fe9f31f955e54799840c26ecbf0213d02020-11-25T01:31:13ZengBMCMolecular Cancer1476-45982018-12-011711710.1186/s12943-018-0924-8Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancerSoon-Ki Hong0Haeseung Lee1Ok-Seon Kwon2Na-Young Song3Hyo-Ju Lee4Seungmin Kang5Jeong-Hwan Kim6Mirang Kim7Wankyu Kim8Hyuk-Jin Cha9College of Pharmacy, Seoul National UniversityDepartment of Life Sciences, Ewha Womans UniversityCollege of Pharmacy, Seoul National UniversityCollege of Pharmacy, Seoul National UniversityCollege of Natural Sciences, Department of Life Sciences, Sogang UniversityDepartment of Life Sciences, Ewha Womans UniversityPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and BiotechnologyPersonalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and BiotechnologyDepartment of Life Sciences, Ewha Womans UniversityCollege of Pharmacy, Seoul National UniversityAbstract 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.http://link.springer.com/article/10.1186/s12943-018-0924-8ChemoresistanceMesenchymal cancerPharmacogenomicsDrug repurposingBiomarkerITGB3 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer Molecular Cancer Chemoresistance Mesenchymal cancer Pharmacogenomics Drug repurposing Biomarker ITGB3 |
author_facet |
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 |
author_sort |
Soon-Ki Hong |
title |
Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer |
title_short |
Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer |
title_full |
Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer |
title_fullStr |
Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer |
title_full_unstemmed |
Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer |
title_sort |
large-scale pharmacogenomics based drug discovery for itgb3 dependent chemoresistance in mesenchymal lung cancer |
publisher |
BMC |
series |
Molecular Cancer |
issn |
1476-4598 |
publishDate |
2018-12-01 |
description |
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. |
topic |
Chemoresistance Mesenchymal cancer Pharmacogenomics Drug repurposing Biomarker ITGB3 |
url |
http://link.springer.com/article/10.1186/s12943-018-0924-8 |
work_keys_str_mv |
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