Acquired Resistance to Crizotinib from a Mutation in CD74–ROS1

• Published in: The New England journal of medicine Vol. 368; no. 25; pp. 2395 - 2401
• Main Authors: Awad, Mark M, Katayama, Ryohei, McTigue, Michele, Liu, Wei, Deng, Ya-Li, Brooun, Alexei, Friboulet, Luc, Huang, Donghui, Falk, Matthew D, Timofeevski, Sergei, Wilner, Keith D, Lockerman, Elizabeth L, Khan, Tahsin M, Mahmood, Sidra, Gainor, Justin F, Digumarthy, Subba R, Stone, James R, Mino-Kenudson, Mari, Christensen, James G, Iafrate, A. John, Engelman, Jeffrey A, Shaw, Alice T
• Format: Journal Article
• Language: English
• Published: Waltham, MA Massachusetts Medical Society 20.06.2013
• Series: Brief Report
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Arginine; Autopsy; Biological and medical sciences; Biopsy; Cancer therapies; Chemotherapy; Clinical trials; Crystal structure; Drug resistance; Drug Resistance - genetics; Dyspnea; Enzyme inhibitors; Fatal Outcome; Female; Gene amplification; General aspects; Glycine; Humans; Inhibitor drugs; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lymphoma; Medical sciences; Metastases; Metastasis; Middle Aged; Mutation; Protein Conformation; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Review boards; Structure-Activity Relationship; Targeted cancer therapy; Translocation; Translocation, Genetic; Tumors; United States > US; Massachusetts; Medicine; Resistance; Genetics; Mutation; Acquired
• ISSN: 0028-4793; 1533-4406; 1533-4406
• DOI: 10.1056/NEJMoa1215530

Crizotinib inhibits various kinases, including ALK and ROS1. In a patient with lung cancer and an activating ROS1 rearrangement, resistance to crizotinib developed early, owing to a mutation that inhibited binding of the drug a few residues away from the classic gatekeeper site. Since the pivotal discovery of imatinib as a safe and effective drug for the treatment of chronic myeloid leukemia, 1 kinase inhibitors have emerged as powerful agents in the treatment of several cancers. The identification of activating mutations within the kinase domain of the epidermal growth factor receptor (EGFR) 2 , 3 has led to the widespread use of kinase inhibitors in this genetically defined subset of lung cancers. 4 More recently, chromosomal translocations that create fusion proteins involving the tyrosine kinase domains of ALK 5 or ROS1 6 have been the subject of intense investigation in lung adenocarcinoma because of the availability of clinically active . . .