Author of

• 20152

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  P1.03 - Chemotherapy/Targeted Therapy (ID 689)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Chemotherapy/Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 22567

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    P1.03-012 - Using Computational Modeling to Simulate Clinical Response of ALK Inhibitors to G1202R ALK and Possible Mechanisms of Resistance (ID 9800)

    09:30 - 09:30  |  Author(s): C. Chen
    • Abstract

    Background:
    Chromosomal inverse translocation of anaplastic lymphoma kinase ( ALK ) have induced constitutively active ALK fusion proteins. Lung cancers with ALK rearrangements are highly sensitive to ALK tyrosine kinase inhibition(TKI). The multi-targeted TKI crizotinib, ceritinib and alectinib were approved by the FDA in 2011 , 2014 and 2015 to treat patients with advanced ALK positive NSCLC. However, most patients develop resistance within 1 to 2 years. The purpose of current study is to utilize computational modeling to simulate clinical response of ALK inhibitors and to investigate possible resistant mechanisms.
    
    Method:
    The X-ray crystal structure of ALK complexed with crizotinib (PDB code 2xp2) was used for the simulations. The residue G1202 was mutated into R1202 by using the SWISS-MODEL software. iGEMDOCK v2.1 was used to generate the docked conformation of ligands and to rank the conformations according to their docking scores. We used its molecular docking platform to dock the crizotinib or ceritinib or alectinib to the active cavity of the ALK models (wild type and mutation type). Molecular dynamic (MD) simulations were performed using the GROMACS package.
    
    Result:
    The trajectories of ligands binding with ALK protein were analyzed for : (a) the root mean square deviation (RMSD) of the activation sites; (b) the pocket distances between the mass center of residues DFG of activation site and the mass center of ligands. The RMSD was found to increase for R1202 ALK protein with three compounds when compared with G1202 ALK protein with crizotinib. By monitoring the pocket distances between the center of residues DFG and the mass center of ligands, we found that the G1202R ALK protein was more open than that of the wild type. Table 1 show docking score using iGEMDOCK v2.1 for three ligands with G1202R ALK protein. Figure 1
    
    
    
    Conclusion:
    Computation modeling may simulate the clinical response but need further investigation.