Journal article
Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1
The New England journal of medicine, Vol.368(25), pp.2395-2401
06/20/2013
DOI: 10.1056/NEJMoa1215530
PMCID: PMC3878821
PMID: 23724914
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.
Details
- Title: Subtitle
- Acquired Resistance to Crizotinib from a Mutation in CD74-ROS1
- Creators
- Mark M. Awad - Massachusetts General HospitalRyohei Katayama - Massachusetts General HospitalMichele McTigue - Pfizer (United States)Wei Liu - Pfizer (United States)Ya-Li Deng - Pfizer (United States)Alexei Brooun - Pfizer (United States)Luc Friboulet - Massachusetts General HospitalDonghui Huang - Pfizer (United States)Matthew D. Falk - Pfizer (United States)Sergei Timofeevski - Pfizer (United States)Keith D. Wilner - Pfizer (United States)Elizabeth L. Lockerman - Massachusetts General HospitalTahsin M. Khan - Massachusetts General HospitalSidra Mahmood - Massachusetts General HospitalJustin F. Gainor - Massachusetts General HospitalSubba R. Digumarthy - Massachusetts General HospitalJames R. Stone - Massachusetts General HospitalMari Mino-Kenudson - Massachusetts Gen Hosp, Ctr Canc, Dept Pathol, Boston, MA 02114 USAJames G. Christensen - Pfizer (United States)A. John Iafrate - Massachusetts General HospitalJeffrey A. Engelman - Massachusetts General HospitalAlice T. Shaw - Massachusetts General Hospital
- Resource Type
- Journal article
- Publication Details
- The New England journal of medicine, Vol.368(25), pp.2395-2401
- DOI
- 10.1056/NEJMoa1215530
- PMID
- 23724914
- PMCID
- PMC3878821
- NLM abbreviation
- N Engl J Med
- ISSN
- 0028-4793
- eISSN
- 1533-4406
- Publisher
- Massachusetts Medical Soc
- Number of pages
- 7
- Grant note
- Pfizer 5R01CA164273-02; R01CA137008; Lung SPORE P50CA090578; a1R21CA161590-01 / National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) V Foundation Translational Research Grant Be a Piece of the Solution Evan Spirito Memorial Foundation
- Language
- English
- Date published
- 06/20/2013
- Academic Unit
- Surgery
- Record Identifier
- 9985224318202771
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