Abstract
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.
Highlights
One of the leading causes of cancer-linked deaths worldwide is attributed to lung cancer [1]
We aimed to identify new drug candidates for treating epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)-resistant lung cancer cells by employing the popular and efficient strategy of drug repurposing, given that new drug development and approval is often protracted and drug attrition rate is notoriously high
The docking results can be openly visualized by accessing http://istar. cse.cuhk.edu.hk/idock/iview/?3W2R-dbap+fda+npc (The Protein Data Bank (PDB) ID 3W2R can be changed to 4I22, 4RJ8, or 5HG7 to view the other docking results using the corresponding protein conformation)
Summary
One of the leading causes of cancer-linked deaths worldwide is attributed to lung cancer [1]. In certain types of NSCLC, the EGFR gene is mutated and becomes constitutively active (i.e., exon 19 deletion or L858R mutation), leading to “addictive” oncogenic signaling [3]. EGFR tyrosine kinase inhibitors (TKIs) target this “addictive” signaling and disrupt the downstream pathways to selectively kill cancer cells. On the other hand, acquired resistance is mainly caused by the induction of a secondary EGFR T790M mutation, which reduces the affinity to EGFR TKIs. Aberrant regulation of parallel oncogenic pathways (MET amplification and HER2 mutation) has been reported. Overexpression of ABC efflux transporters (P-gp and ABCG2) leads to acquired resistance [5] To this end, most EGFR TKIs are known substrates of these transporters [6, 7]. Gefitinib and erlotinib are only suggested for the treatment of NSCLC patients if they harbor activating EGFR mutations without the resistance mechanisms. Intense research efforts have been made to search for alternative treatment options for patients who have resistance to EGFR TKIs [8, 9]
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