title: Selectivity profile of afatinib for EGFR-mutated non-small-cell lung cancer.
abstract: EGFR-mutated non-small-cell lung cancer (NSCLC) has long been a research focus in lung cancer studies. Besides reversible tyrosine kinase inhibitors (TKIs), new-generation irreversible inhibitors, such as afatinib, embark on playing an important role in NSCLC treatment. To achieve an optimal application of these inhibitors, the correlation between the EGFR mutation status and the potency of such an inhibitor should be decoded. In this study, the correlation was profiled for afatinib, based on a cohort of patients with the EGFR-mutated NSCLC. Relying on extracted DNAs from the paraffin-embedded tumor samples, EGFR mutations were detected by direct sequencing. Progression-free survival (PFS) and the response level were recorded as study endpoints. These PFS and response values were analyzed and correlated to different mutation types, implying a higher potency of afatinib to classic activation mutations (L858R and deletion 19) and a lower one to T790M-related mutations. To further bridge the mutation status with afatinib-related response or PFS, we conducted a computational study to estimate the binding affinity in a mutant-afatinib system, based on molecular structural modeling and dynamics simulations. The derived binding affinities were well in accordance with the clinical response or PFS values. At last, these computational binding affinities were successfully mapped to the patient response or PFS according to linear models. Consequently, a detailed mutation-response or mutation-PFS profile was drafted for afatinib, implying the selective nature of afatinib to various EGFR mutants and further encouraging the design of specialized therapies or innovative drugs.
authors.affiliation: Caritas Institute of Higher Education, 18 Chui Ling Road, New Territories, Hong Kong, China. danwang6-c@my.cityu.edu.hk and Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong, China.
authors.forename: Debby D
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China. vhflee@hku.hk.
authors.forename: Victor H F
authors.initials: VH
authors.lastname: Lee
authors.affiliation: Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong, China. guangzhu@cityu.edu.hk.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zou
authors.affiliation: Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong, China.
authors.forename: Lichun
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
mesh_terms: D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009154:Mutation; D011379:Prognosis; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D066246:ErbB Receptors