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Int. J. Mol. Sci. 2017, 18(3), 482; doi:10.3390/ijms18030482

L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites

School of Medicine, Chengdu University, Chengdu 610106, China
College of Life Sciences and Key Laboratory for Bio-Resources of Ministry of Education, Sichuan University, Chengdu 610064, China
School of Information Science and Engineering, Chengdu University, Chengdu 610106, China
Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China
College of Pharmacy and Biological Engineering, Chengdu University, Chengdu 610106, China
Authors to whom correspondence should be addressed.
Academic Editor: Tatyana Karabencheva-Christova
Received: 9 January 2017 / Revised: 1 February 2017 / Accepted: 18 February 2017 / Published: 24 February 2017
(This article belongs to the Collection Proteins and Protein-Ligand Interactions)
View Full-Text   |   Download PDF [7311 KB, uploaded 24 February 2017]   |  


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. View Full-Text
Keywords: ALK; point mutation; drug resistance; resensitization; lorlatinib ALK; point mutation; drug resistance; resensitization; lorlatinib

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Li, J.; Sun, R.; Wu, Y.; Song, M.; Li, J.; Yang, Q.; Chen, X.; Bao, J.; Zhao, Q. L1198F Mutation Resensitizes Crizotinib to ALK by Altering the Conformation of Inhibitor and ATP Binding Sites. Int. J. Mol. Sci. 2017, 18, 482.

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