title: Mapping inhibitor response to the in-frame deletions, insertions and duplications of epidermal growth factor receptor (EGFR) in non-small cell lung cancer.
abstract: Human epidermal growth factor receptor (EGFR) has become a well-established target for the treatment of non-small cell lung cancer (NSCLC). However, a large number of in-frame deletion, insertion and duplication mutations in the EGFR tyrosine kinase (TK) domain have been observed to alter drug response to such a kinase target. Thus, a systematic investigation of the intermolecular interactions between the clinical small-molecule agents and various EGFR in-frame mutants would help to establish a complete picture of drug response to kinase mutations in lung cancer, and to design new EGFR inhibitors with high potency and selectivity to target drug-resistant mutants. Here, we describe a combined pipeline to explore the drug response of five representative EGFR inhibitors, including three FDA-approved agents (gefitinib, erlotinib and lapatinib) and two compounds under clinical development (AEE788 and TAK-285) to a number of clinically relevant EGFR in-frame mutations, aiming at a comprehensive understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity to EGFR in-frame mutations. It was found that the insertion and duplication mutations in exon 20 can generally cause drug resistance to EGFR due to the reduced size of kinase's active pocket, while deletion mutations in exon 19 associate closely with increased inhibitor sensitivity to EGFR by establishing additional non-bonded interactions across complex interface, including hydrogen bonds, cation-π interactions and hydrophobic contacts.
authors.affiliation: a Department of Chemistry , Zhejiang University , Hangzhou , P. R. China .|b School of Chemical and Biological Engineering, Changsha University of Science & Technology , Changsha , P. R. China , and.
authors.forename: Jingheng
authors.initials: J
authors.lastname: Ning
authors.affiliation: a Department of Chemistry , Zhejiang University , Hangzhou , P. R. China .
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.affiliation: c Department of Infectious Diseases , The Third Xiangya Hospital, Central South University , Changsha , P. R. China.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: b School of Chemical and Biological Engineering, Changsha University of Science & Technology , Changsha , P. R. China , and.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Wang
authors.affiliation: a Department of Chemistry , Zhejiang University , Hangzhou , P. R. China .
authors.forename: Xianfu
authors.initials: X
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016254:Mutagenesis, Insertional; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Drug resistance and sensitivity; epidermal growth factor receptor; in-frame mutation; kinase inhibitor; non-small cell lung cancer