Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors Journal Article


Authors: Davare, M. A.; Vellore, N. A.; Wagner, J. P.; Eide, C. A.; Goodman, J. R.; Drilon, A.; Deininger, M. W.; O'Hare, T.; Druker, B. J.
Article Title: Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors
Abstract: Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1- and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib's dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure-function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK-driven NSCLC and other malignancies.
Keywords: unclassified drug; drug efficacy; protein domain; molecular dynamics; inhibitor; drug design; drug selectivity; protein tyrosine kinase inhibitor; binding site; drug sensitivity; phosphotransferase; drug protein binding; alk; anaplastic lymphoma kinase; kinase; crizotinib; cabozantinib; foretinib; ros1; protein ros1; priority journal; article; ceritinib; alectinib; structural modelling; anaplastic lymphoma kinase inhibitor; azd 3463; brigatinib
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 112
Issue: 39
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2015-09-29
Start Page: E5381
End Page: E5390
Language: English
DOI: 10.1073/pnas.1515281112
PROVIDER: scopus
PMCID: PMC4593101
PUBMED: 26372962
DOI/URL:
Notes: Export Date: 2 November 2015 -- Source: Scopus
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  1. Alexander Edward Drilon
    424 Drilon