In silico identification and experimental validation of clinically approved drugs to treat molecular targeted drug-resistant lung cancer cells
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AbstractThe goal of this study is (i) to identify clinically used drug candidates for repurposing to treat lung cancer cells resistant to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) by in silico docking simulation; and (ii) to validate the chosen drug candidates in cancer cell models. Drug repurposing is the application of clinically approved drugs, with optimized dosing regimens and known side effect profiles, to new indications. EGFR TKIs have unprecedented clinical efficacy in advanced lung cancer. 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 domain and thereby abolishing the therapeutic efficacy.

In this study, we have used our in-house developed protein-ligand docking software “idock” ( to screen FDA-approved small molecule drugs against EGFR bearing the resistance-causing mutations. The computationally selected drug candidates were evaluated in vitro in non-small cell lung cancer (NSCLC) cell lines resistant to EGFR TKIs. Mechanistic studies were performed to investigate the specificity of the compounds towards inhibiting the kinase activity of the various EGFR mutants, and induction of apoptosis.

Based on the simulation score, thirty-six drug candidates were chosen from the in silico screening for in vitro evaluation in NSCLC bearing wild-type EGFR, EGFR L858R (sensitizing mutation), or EGFR L858R/T790M (resistance-causing mutation). Three drugs were found to exhibit anticancer activity in the cancer cells and two of them were more potent in NSCLC harboring EGFR L858R/T790M than those with EGFR L858R. Their specificity towards inhibiting EGFR L858R/T790M were further confirmed by cell-free biochemical kinase assay and Western blot analysis in the NSCLC cell models. The positive hits were also showed to inhibit the EGFR-PI3K-Akt signaling pathway and cause apoptosis. Interestingly, the drug candidates identified also gave rise to pronounced synergistic anticancer activity specifically in NSCLC cells harboring EGFR T790M when used in combination with gefitinib.

The drug candidates identified may be repurposed for treating NSCLC resistant to EGFR TKIs. The same in silico screening approach may be used to hunt for other clinically used drugs for repurposing to treat cancer cells resistant to other molecular targeted agents.
Acceptance Date17/01/2017
All Author(s) ListTo KK, Li HJ, Leung KS
Name of ConferenceAmerican Association for Cancer Research (AACR) Annual Meeting 2017
Start Date of Conference01/04/2017
End Date of Conference05/04/2017
Place of ConferenceWashington D.C., U.S.A.
Country/Region of ConferenceUnited States of America
Proceedings TitleProceedings of the American Association for Cancer Research AACR Annual Meeting 2017
Volume Number58
PublisherAmerican Association for Cancer Research
LanguagesEnglish-United States
KeywordsRepurposing, in silico screening, molecular targeted drug, drug resistance, lung cancer

Last updated on 2018-22-01 at 05:54