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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
A molecular dynamics investigation on the crizotinib resistance mechanism of C1156Y mutation in ALK
1Shandong University of Technology, Zibo 255049, PR China.
Abstract:
Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor that has recently been approved in the US for the treatment of non-small cell lung carcinoma (NSCLC). Despite its outstanding safety and efficacy, several resistant mutations against crizotinib have been detected in the treatment of NSCLC. However, in contrast to the widely accepted mechanism of steric hindrance by mutations at the active site, the mechanism by which the C1156Y non-active site mutation confers resistance against crizotinib remains unclear. In the present study, the resistance mechanism of C1156Y in ALK was investigated using molecular dynamics simulations. The results suggest that despite the non-active site mutation, C1156Y causes the dislocation of crizotinib as well as the indirect conformational changes in the binding cavity, which results in a marked decrease in the van der Waals and electrostatic interactions between crizotinib and ALK. The obtained results provide a detailed explanation of the resistance caused by C1156Y and may give a vital clue for the design of drugs to combat crizotinib resistance.
Insights
The C1156Y mutation in anaplastic lymphoma kinase (ALK) confers crizotinib resistance in non-small cell lung cancer by altering drug binding. This study reveals indirect conformational changes causing crizotinib dislocation and reduced interactions.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Crizotinib is an FDA-approved anaplastic lymphoma kinase (ALK) inhibitor for non-small cell lung cancer (NSCLC).
- Emergence of drug-resistant mutations, including non-active site mutations like C1156Y, poses a significant challenge in NSCLC treatment.
- The precise mechanism of resistance conferred by the C1156Y mutation remains incompletely understood, contrasting with known active site steric hindrance mechanisms.
Purpose of the Study:
- To elucidate the molecular mechanism by which the C1156Y mutation in ALK confers resistance to crizotinib in NSCLC.
- To investigate the impact of the C1156Y mutation on the binding interactions and conformational dynamics of ALK with crizotinib.
Main Methods:
- Utilized molecular dynamics (MD) simulations to investigate the resistance mechanism of the C1156Y mutation in ALK.
- Analyzed changes in drug binding, conformational dynamics, and intermolecular interactions between crizotinib and ALK.
Main Results:
- The C1156Y mutation, despite being in a non-active site region, induces dislocation of crizotinib from the ALK binding pocket.
- This mutation leads to indirect conformational alterations within the ALK binding cavity.
- A significant reduction in van der Waals and electrostatic interactions between crizotinib and ALK was observed due to the C1156Y mutation.
Conclusions:
- The C1156Y mutation confers crizotinib resistance through indirect conformational changes and drug dislocation, rather than direct steric hindrance at the active site.
- These findings provide a detailed mechanistic explanation for C1156Y-mediated resistance in ALK-mutated NSCLC.
- The study offers crucial insights for the rational design of next-generation inhibitors to overcome crizotinib resistance.
