title: L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites.
abstract: The efficacy of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC) treatment with small molecule inhibitors is greatly challenged by acquired resistance. A recent study reported the newest generation inhibitor resistant mutation L1198F led to the resensitization to crizotinib, which is the first Food and Drug Administration (FDA) approved drug for the treatment of ALK-positive NSCLC. It is of great importance to understand how this extremely rare event occurred for the purpose of overcoming the acquired resistance of such inhibitors. In this study, we exploited molecular dynamics (MD) simulation to dissect the molecular mechanisms. Our MD results revealed that L1198F mutation of ALK resulted in the conformational change at the inhibitor site and altered the binding affinity of ALK to crizotinib and lorlatinib. L1198F mutation also affected the autoactivation of ALK as supported by the identification of His1124 and Tyr1278 as critical amino acids involved in ATP binding and phosphorylation. Our findings are valuable for designing more specific and potent inhibitors for the treatment of ALK-positive NSCLC and other types of cancer.
authors.affiliation: School of Medicine, Chengdu University, Chengdu 610106, China. lijian01@cdu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. sunrong198982@163.com.
authors.forename: Rong
authors.initials: R
authors.lastname: Sun
authors.affiliation: School of Information Science and Engineering, Chengdu University, Chengdu 610106, China. yuehongwu.cdu@foxmail.com.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Medicine, Chengdu University, Chengdu 610106, China. songmingzhu@cdu.edu.cn.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Song
authors.affiliation: School of Medicine, Chengdu University, Chengdu 610106, China. lijia0619@foxmail.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China. qianyeyang@foxmail.com.
authors.forename: Qianye
authors.initials: Q
authors.lastname: Yang
authors.affiliation: College of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China. xiaoyichen.cdu@foxmail.com.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Chen
authors.affiliation: College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China. baojinku@scu.edu.cn.
authors.forename: Jinku
authors.initials: J
authors.lastname: Bao
authors.affiliation: College of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China. zhaoqi@cdu.edu.cn.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000596:Amino Acids / Q000737:chemistry; D000077548:Anaplastic Lymphoma Kinase; D001665:Binding Sites; D003062:Codon; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D003062:Codon; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D000255:Adenosine Triphosphate; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; drug resistance; lorlatinib; point mutation; resensitization