Abstract 46P
Background
The oncogenic potential of c-ros oncogene 1 (ROS1) has been established recently, especially in rare non-small cell lung cancer (NSCLC) patients with hallmark ROS1 gene-fusions. The fused gene partners often dictate the localisation whereas the conserved kinase domain ensures a constitutively activated kinase. Personalized, anti-cancer therapies using tyrosine kinase inhibitors (TKIs) have achieved success in the past for related kinase targets, including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). This targeted approach has been translated to ROS1, but the overall success is greatly affected by kinase domain resistance mutations.
Methods
Due to lack of ROS1 experimental structures in the inactive (DFG-out) state, we employ homology modelling using a related template, c-ABL kinase structure (PDB entry 1IEP), to model inactive ROS1 wild-type (WT) and mutant structures. These models are then subjected to molecular docking to generate protein-ligand complexes with type 2 TKIs. Obtained complexes are evaluated by all-atom molecular dynamic (MD) simulations.
Results
The ROS1 DFG-out state models for the WT and two mutants, F2004C and F2004V (in proximity of αC-helix), were successfully evaluated using key features distinguishing active and inactive states. The starting models showed clear differences for selected distance and angle-based calculations. This provided the structural basis to study type 2 TKIs bound to the inactive ROS1 receptor and to evaluate the effect of resistance mutations in the absence of experimental structural information.
Conclusions
The findings from this computational exploration contribute valuable insights into structural dynamics of the ROS1 kinase domain, the impact of point mutations near key regulatory regions, and protein-ligand interaction profiles with inactive-kinase specific TKIs.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Fonds Wetenschappelijk Onderzoek - Vlaanderen; Stichting Kom Op Tegen Kanker.
Disclosure
All authors have declared no conflicts of interest.