In silico insight into EGFR treatment in patients with lung carcinoma and T790M mutations

Abstract

The T790M mutational basis of treatment failure, following treatment via alteration of the epidermal growth factor receptor (EGFR) pathway, is a well-known anomaly in patients with non-small cell lung cancer (NSCLC). The T790M mutation activates the kinase domain, causing tyrosine kinase inhibitors, such as gefitinib, to elicit little or no response. To overcome this acquired resistance in NSCLC cells, the present study utilized a structure-based drug designing method to identify a novel lead compound. An in-house traditional Chinese medicinal compound database was used and following initial virtual screening, pre-absorption, distribution, metabolism and excretion/Tox and automated docking analyses, nardosinon was selected as the most appropriate candidate for further analysis. Two NSCLC cell lines, PC9GR4 and H2347, were used to test nardosinon and the results were compared with gefitinib. Results from an initial cell death assay revealed that nardosinon was able to induce cell death in NSCLC cells with and without the T790M mutation. These findings suggest that nardosinon may be an effective pharmacological compound for NSCLC treatment, including T790M EGFR mutant NSCLC cells.

Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

“…The auto-phosphorylation is due to the catalytic reaction, which converts the ATP and the l-tyrosyl in the EGFR to ADP and O-phospho-l-tyrosyl [35]. This cascade is responsible for the activation in the cell proliferation cycle in NSCLC through RAS/RAF/mitogen-activated protein kinase (MAPK) pathway, which is important for the regulation of cell survival.…”

“…This cascade is responsible for the activation in the cell proliferation cycle in NSCLC through RAS/RAF/mitogen-activated protein kinase (MAPK) pathway, which is important for the regulation of cell survival. The cascade indirectly activates phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), which causes inhibition of apoptosis and cancerous growth [35] (Fig. 1).…”

“…When ligand interacts with TK, conformational changes occur in the receptor, which leads to auto-phosphorylation of complex formed which further initiates signal transduction cascade. The auto-phosphorylation is due to the catalytic reaction, which converts the ATP and the l -tyrosyl in the EGFR to ADP and O -phospho- l -tyrosyl [ 35 ]. This cascade is responsible for the activation in the cell proliferation cycle in NSCLC through RAS/RAF/mitogen-activated protein kinase (MAPK) pathway, which is important for the regulation of cell survival.…”

“…The diagram highlights the important markers like RAS, RAF, ERK, PI3K, AKT, and mTOR of the disease and the mechanism of action of drugs against NSCLC (details refer to text and ref. 33 – 35 ) …”

Inhibiting Two Cellular Mutant Epidermal Growth Factor Receptor Tyrosine Kinases By Addressing Computationally Assessed Crystal Ligand Pockets

“…To address EGFR drug resistance, virtual screening based on the crystal structures of EGFR-TK complexed with inhibitors [12][13][14] provides an efficient way to identify potential therapeutic combinations. Several virtual screening approaches using molecular docking for wild-type or mutant EGFR-TKI followed by experimental confirmation have been reported in recent years [15][16][17][18][19][20]. To improve the identification of potential hits by virtual screening, kinase-focused libraries [17], natural product databases [20] and homology binding pockets [19] have been constructed beforehand for screening.…”