Another great find from shimoda today
Acquired resistance to crizotinib from a mutation in CD74-ROS1.
AuthorsAwad MM, et al. Show all Journal
N Engl J Med. 2013 Jun 20;368(25):2395-401. doi: 10.1056/NEJMoa1215530. Epub 2013 Jun 1.
Affiliation
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
Abstract
Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
PMID 23724914 [PubMed - indexed for MEDLINE]
Full text: Atypon
Related CitationsShow all
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
Molecular Pathways: ROS1 Fusion Proteins in Cancer.
