Contribution of EGFR and ErbB-3 Heterodimerization to the EGFR Mutation-Induced Gefitinib- and Erlotinib-Resistance in Non-Small-Cell Lung Carcinoma Treatments

Abstract

EGFR mutation-induced drug resistance has become a major threat to the treatment of non-small-cell lung carcinoma. Essentially, the resistance mechanism involves modifications of the intracellular signaling pathways. In our work, we separately investigated the EGFR and ErbB-3 heterodimerization, regarded as the origin of intracellular signaling pathways. On one hand, we combined the molecular interaction in EGFR heterodimerization with that between the EGFR tyrosine kinase and its inhibitor. For 168 clinical subjects, we characterized their corresponding EGFR mutations using molecular interactions, with three potential dimerization partners (ErbB-2, IGF-1R and c-Met) of EGFR and two of its small molecule inhibitors (gefitinib and erlotinib). Based on molecular dynamics simulations and structural analysis, we modeled these mutant-partner or mutant-inhibitor interactions using binding free energy and its components. As a consequence, the mutant-partner interactions are amplified for mutants L858R and L858R_T790M, compared to the wild type EGFR. Mutant delL747_P753insS represents the largest difference between the mutant-IGF-1R interaction and the mutant-inhibitor interaction, which explains the shorter progression-free survival of an inhibitor to this mutant type. Besides, feature sets including different energy components were constructed, and efficient regression trees were applied to map these features to the progression-free survival of an inhibitor. On the other hand, we comparably examined the interactions between ErbB-3 and its partners (EGFR mutants, IGF-1R, ErbB-2 and c-Met). Compared to others, c-Met shows a remarkably-strong binding with ErbB-3, implying its significant role in regulating ErbB-3 signaling. Moreover, EGFR mutants corresponding to poor clinical outcomes, such as L858R_T790M, possess lower binding affinities with ErbB-3 than c-Met does. This may promote the communication between ErbB-3 and c-Met in these cancer cells. The analysis verified the important contribution of IGF-1R or c-Met in the drug resistance mechanism developed in lung cancer treatments, which may bring many benefits to specialized therapy design and innovative drug discovery.

Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and PDGFR-β related to anticancer drug resistance

“…However, novel inhibitors of EGFR are suspected to suffer from similar anticancer drug resistances than the established inhibitors. Beside so far unknown mutations which may affect the inhibitor binding to EGFR, another mechanism of drug resistance may lower the inhibitor activity: a receptor heterodimerization 12 . Normally, the ligand-activated EGFR undergoes a receptor dimerisation with a neighboured EGFR receptor 13 .…”

Expression and clinical significance of microRNA‑21, PTEN and p27 in cancer tissues of patients with non‑small cell lung cancer

“…The human epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTKs) and plays an important role in the pathogenesis and progression of different cancers, thus it has become a major subject for scholars ( 27 , 28 ). In the study by Wang et al ( 29 ), EGFR mutation-induced drug resistance has become a major threat to the treatment of NSCLC; the resistance mechanism involves the modification of intracellular signaling pathways. According to Xu et al ( 30 ), molecular genetic analysis showed that KRAS mutations were frequent in NSCLC.…”

Discovery of novel dual inhibitors of receptor tyrosine kinases EGFR and IGF-1R

“…Mutations that cause exchanges of such amino acids led to resistance developments against established inhibitors 22 . Another recently discovered resistance mechanism of cancer cells is a possible heterodimerization of the EGFR receptor with IGF-1R as another activated tyrosine kinase 23 , 24 . Such described heterodimerizations made void the EGFR-specific inhibitory activity of an established EGFR inhibitor.…”