Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer
In advanced lung cancer, epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) have extraordinary clinical efficacy. However, their usefulness is severely compromised by drug resistance mediated by various mechanisms, the most important of which is the secondary EGFR T790M mutation. The mut...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fonc.2017.00288/full |
| _version_ | 1818005999926116352 |
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| author | Hongjian Li Hongjian Li Christy Wing-Sum Tong Yee Leung Man-Hon Wong Kenneth Kin-Wah To Kwong-Sak Leung Kwong-Sak Leung |
| author_facet | Hongjian Li Hongjian Li Christy Wing-Sum Tong Yee Leung Man-Hon Wong Kenneth Kin-Wah To Kwong-Sak Leung Kwong-Sak Leung |
| author_sort | Hongjian Li |
| collection | DOAJ |
| description | In advanced lung cancer, epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) have extraordinary clinical efficacy. However, their usefulness is severely compromised by drug resistance mediated by various mechanisms, the most important of which is the secondary EGFR T790M mutation. The mutation blocks the binding of EGFR TKIs to the receptor kinase, thereby abolishing the therapeutic efficacy. In this study, we used our free and open-source protein-ligand docking software idock to screen worldwide approved small-molecule drugs against EGFR T790M. The computationally selected drug candidates were evaluated in vitro in resistant non-small cell lung cancer (NSCLC) cell lines. The specificity of the drugs toward the mutant EGFR was demonstrated by cell-free kinase inhibition assay. The inhibition of EGFR kinase activity and its downstream signaling pathways in NSCLC cells was shown by immunoblot analysis. The positive hints were revealed to be indacaterol, canagliflozin, and cis-flupenthixol, all of which were shown to induce apoptosis in NSCLC cells harboring the EGFR T790M mutation. Moreover, the combination of indacaterol with gefitinib was also found to produce synergistic anticancer effect in NSCLC cells bearing EGFR T790M. The observed synergistic effect was likely contributed by the enhanced inhibition of EGFR and its downstream signaling molecules. |
| first_indexed | 2024-04-14T04:54:29Z |
| format | Article |
| id | doaj.art-f58ebdf886984dc690e1424f0cccebfb |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-14T04:54:29Z |
| publishDate | 2017-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f58ebdf886984dc690e1424f0cccebfb2022-12-22T02:11:12ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2017-11-01710.3389/fonc.2017.00288310520Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung CancerHongjian Li0Hongjian Li1Christy Wing-Sum Tong2Yee Leung3Man-Hon Wong4Kenneth Kin-Wah To5Kwong-Sak Leung6Kwong-Sak Leung7Institute of Future Cities, The Chinese University of Hong Kong, Hong Kong, Hong KongDepartment of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, Hong KongFaculty of Medicine, School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, Hong KongInstitute of Future Cities, The Chinese University of Hong Kong, Hong Kong, Hong KongDepartment of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, Hong KongFaculty of Medicine, School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, Hong KongInstitute of Future Cities, The Chinese University of Hong Kong, Hong Kong, Hong KongDepartment of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong, Hong KongIn advanced lung cancer, epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) have extraordinary clinical efficacy. However, their usefulness is severely compromised by drug resistance mediated by various mechanisms, the most important of which is the secondary EGFR T790M mutation. The mutation blocks the binding of EGFR TKIs to the receptor kinase, thereby abolishing the therapeutic efficacy. In this study, we used our free and open-source protein-ligand docking software idock to screen worldwide approved small-molecule drugs against EGFR T790M. The computationally selected drug candidates were evaluated in vitro in resistant non-small cell lung cancer (NSCLC) cell lines. The specificity of the drugs toward the mutant EGFR was demonstrated by cell-free kinase inhibition assay. The inhibition of EGFR kinase activity and its downstream signaling pathways in NSCLC cells was shown by immunoblot analysis. The positive hints were revealed to be indacaterol, canagliflozin, and cis-flupenthixol, all of which were shown to induce apoptosis in NSCLC cells harboring the EGFR T790M mutation. Moreover, the combination of indacaterol with gefitinib was also found to produce synergistic anticancer effect in NSCLC cells bearing EGFR T790M. The observed synergistic effect was likely contributed by the enhanced inhibition of EGFR and its downstream signaling molecules.http://journal.frontiersin.org/article/10.3389/fonc.2017.00288/fullepidermal growth factor tyrosine kinase inhibitor resistancedockingdrug repurposingindacaterolcanagliflozincis-flupenthixol |
| spellingShingle | Hongjian Li Hongjian Li Christy Wing-Sum Tong Yee Leung Man-Hon Wong Kenneth Kin-Wah To Kwong-Sak Leung Kwong-Sak Leung Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer Frontiers in Oncology epidermal growth factor tyrosine kinase inhibitor resistance docking drug repurposing indacaterol canagliflozin cis-flupenthixol |
| title | Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer |
| title_full | Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer |
| title_fullStr | Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer |
| title_full_unstemmed | Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer |
| title_short | Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer |
| title_sort | identification of clinically approved drugs indacaterol and canagliflozin for repurposing to treat epidermal growth factor tyrosine kinase inhibitor resistant lung cancer |
| topic | epidermal growth factor tyrosine kinase inhibitor resistance docking drug repurposing indacaterol canagliflozin cis-flupenthixol |
| url | http://journal.frontiersin.org/article/10.3389/fonc.2017.00288/full |
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