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

• Published in: PloS one Vol. 10; no. 5; p. e0128360
• Main Authors: Wang, Debby D., Ma, Lichun, Wong, Maria P., Lee, Victor H. F., Yan, Hong
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.05.2015; Public Library of Science (PLoS)
• Subjects: Analysis; Binding; Binding sites; Breast cancer; c-Met protein; Cancer; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Care and treatment; Cell growth; Computational chemistry; Computer simulation; Development and progression; Dimerization; Disease-Free Survival; Drug development; Drug discovery; Drug resistance; Drug Resistance, Neoplasm - genetics; Dynamic structural analysis; Energy consumption; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; ErbB protein; ErbB-2 protein; ErbB-3 protein; Erlotinib; Erlotinib Hydrochloride - pharmacology; Erlotinib Hydrochloride - therapeutic use; Free energy; Gefitinib; Genetic aspects; Health aspects; Humans; Inhibitor drugs; Inhibitors; Insulin-like growth factors; Intracellular; Intracellular signalling; Kinases; Ligands; Lung cancer; Lung cancer, Non-small cell; Lung carcinoma; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medical innovations; Medical research; Molecular dynamics; Molecular Dynamics Simulation; Molecular interactions; Mutant Proteins - chemistry; Mutants; Mutation; Mutation - genetics; Non-small cell lung carcinoma; Protein Binding - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Multimerization - drug effects; Protein-tyrosine kinase; Proteins; Quinazolines - pharmacology; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - chemistry; Receptor, Epidermal Growth Factor - genetics; Receptor, ErbB-3 - metabolism; Regression Analysis; Rodents; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Structural analysis; Structural Homology, Protein; Studies; Survival; Targeted cancer therapy; Thermodynamics; Tyrosine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128360

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.