ABSTRACT
Abstract As a major type of lung cancer, non-small-cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Gene mutations affecting the catalytic activity of epidermal growth factor receptor (EGFR) normally promote NSCLC. In clinical treatments of NSCLC, tyrosine kinase inhibitors (TKIs) are broadly used to target the kinase domain of mutated EGFR. Although these drugs are effective initially, drug resistance rapidly emerges. Studies on the resistance mechanism can be guided by the dissection of EGFR signaling network, and computational approaches play a significant role. One general research focus is calculating the binding affinity of an EGFR mutant and a TKI, which can be characterized by the free energy of binding, interfacial hydrogen bonds, and shape complementation of interfaces. Another important research direction is investigating the modified molecular interactions in the EGFR downstream signaling pathways, and EGFR dimerization is a valuable segment. Specifically in our studies, techniques such as molecular dynamics (MD) simulations, three-dimensional molecular modeling and structural analysis, were applied. Binding affinities between each EGFR mutant and a partner were evaluated based on these techniques. Recently, dually-targeted TKIs (target dual receptors) and second-generation TKIs (covalently bound to the mutated EGFR kinase) are proposed, to combat drug resistance in clinical treatments of NSCLC. However, the risk of underlying drug resistance still exists. To decode these new mechanisms, computational modeling remains indispensable. Overall, these studies can encourage the development of new-generation and more sophisticated drugs, and further help the design of specialized therapies in NSCLC treatments.
