title: Acquired resistance to crizotinib from a mutation in CD74-ROS1.
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.).
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.forename: Michele
authors.initials: M
authors.lastname: McTigue
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Deng
authors.forename: Alexei
authors.initials: A
authors.lastname: Brooun
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.forename: Donghui
authors.initials: D
authors.lastname: Huang
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Falk
authors.forename: Sergei
authors.initials: S
authors.lastname: Timofeevski
authors.forename: Keith D
authors.initials: KD
authors.lastname: Wilner
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Lockerman
authors.forename: Tahsin M
authors.initials: TM
authors.lastname: Khan
authors.forename: Sidra
authors.initials: S
authors.lastname: Mahmood
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.forename: Subba R
authors.initials: SR
authors.lastname: Digumarthy
authors.forename: James R
authors.initials: JR
authors.lastname: Stone
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077547:Crizotinib; D004351:Drug Resistance / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D014178:Translocation, Genetic
chemical_list: D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human