Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

Abstract

Non-small cell lung cancer (NSCLC) represents a difficult condition to treat, due to epidermal growth factor receptor (EGFR) kinase domain mutations, which lead to ligand-independent phosphorylation. Deletion of five amino acids (ELREA) in exon 19 and mutational change from leucine to arginine at position 858 (L858R) are responsible for tyrosine kinase domain aberrant activation. These two common types of EGFR-mutated forms are clinically associated with high response with Tyrosine Kinase Inhibitors (TKI); however, the secondary T790M mutation within the Tyrosine Kinase Domain (TKD) determines a resistance to these EGFR-TKIs. Using molecular dynamic simulation (MD), the present study investigated the architectural changes of wild-type and mutants EGFR’s kinase domains in order to detect any conformational differences that could be associated with a constitutively activated state and thus to evaluate the differences between the wild-type and its mutated forms. In addition, in order to evaluate to which extent the EGFR mutations affect its inhibition, Epigallocatechin 3-Gallate (EGCG) and Erlotinib (Erl), known EGFR-TKI, were included in our study. Their binding modes with the EGFR-TK domain were elucidated and the binding differences between EGFR wild-type and the mutated forms were evidenced. The aminoacids mutations directly influence the binding affinity of these two inhibitors, resulting in a different efficacy of Erl and EGCG inhibition. In particular, for the T790M/L858R EGFR, the binding modes of studied inhibitors were compromised by aminoacidic substitution confirming the experimental findings. These results may be useful for novel drug design strategies targeting the dimerization domain of the EGFR mutated forms, thus preventing receptor activation.

Modulation of Autophagy in Cancer Cells by Dietary Polyphenols

“…Moreover, they have been suggested to play an important role in the prevention of cancer diseases [ 66 , 71 , 78 ]. The biologically active ingredients of fruits and vegetables, described in this review, such as the main catechin of green tea, EGCG [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ], oleuropein [ 49 , 50 , 51 , 52 , 53 ], punicalgin [ 39 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ], apigenin [ 40 , 77 , 78 , 79 , 80 ], resveratrol [ …”

“…Thus, dietary polyphenols alone may not have a significant effect on the growth of neoplastic cells, but will prove useful in combination therapy with cytostatic drugs to increase the effectiveness of oncological therapy [ 53 ]. Activating mutations in the EGFR gene in both wild-type and the mutant forms T790M, L858R, and ELREA are often found in NSCLC patients [ 54 ]. Experimental studies were carried out with the use of EGCG and EGFR-TKI (erlotinib) [ 54 ].…”

“…Activating mutations in the EGFR gene in both wild-type and the mutant forms T790M, L858R, and ELREA are often found in NSCLC patients [ 54 ]. Experimental studies were carried out with the use of EGCG and EGFR-TKI (erlotinib) [ 54 ]. Positive results of the experiment such as in clarifying the differences in the bonds of both wild-type EGFR and mutant types, indicate that the use of polyphenols in the diet may affect the growth of cancer cells, which at the same time is an important aspect as adjunctive therapy [ 54 ].…”

Effects of Infusion and Storage on Antioxidant Activity and Total Phenolic Content of Black Tea

“…Theaflavins, a type of phenolic compound in black tea, may contribute to strong antioxidant properties that affect the DPPH scavenging activity and total phenols [23,[29][30][31][32]. However, the therapeutic activities of black tea are attributed not only to the antioxidant activity of its components but also to the ability of bioactive molecules to interact with several biological targets [33,34]. At a high temperature, chemical degradation can occur, changing the structure of temperature-sensitive molecules such as (-)-epigallocatechin-3-gallate.…”

Fatty Acid Synthase Inhibitor G28 Shows Anticancer Activity in EGFR Tyrosine Kinase Inhibitor Resistant Lung Adenocarcinoma Models

“…Some authors exposed that the mechanism underlying EGCG antitumor potency is due to the suppression of the EGFR signaling pathway in NSCLC [52]. Others observed a very stable complex between EGCG and EGFRm (exon 19 ELREA deletion) that was lost with the T790M substitution [53]. Kozue and coworkers showed that EGCG reduced stemness and immunogenicity in EGFR wild type NSCLC cells in vitro and in vivo through the inhibition of AXL [54].…”