title: 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.
authors.affiliation: Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Debby D
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Lichun
authors.initials: L
authors.lastname: Ma
authors.affiliation: Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Wong
authors.affiliation: Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Victor H F
authors.initials: VH
authors.lastname: Lee
authors.affiliation: Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D055503:Protein Multimerization / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D012044:Regression Analysis; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D000077156:Gefitinib