title: A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged Lung Cancer.
abstract: Rearranged ROS1 is a crizotinib-sensitive oncogenic driver in lung cancer. The development of acquired resistance, however, poses a serious clinical challenge. Consequently, experimental and clinical validation of resistance mechanisms and potential second-line therapies is essential.
  
  
  
  We report the discovery of a novel, solvent-front ROS1(D2033N) mutation in a patient with CD74-ROS1-rearranged lung adenocarcinoma and acquired resistance to crizotinib. Crizotinib resistance of CD74-ROS1(D2033N) was functionally evaluated using cell-based assays and structural modeling.
  
  
  
  In biochemical and cell-based assays, the CD74-ROS1(D2033N) mutant demonstrated significantly decreased sensitivity to crizotinib. Molecular dynamics simulation revealed compromised crizotinib binding due to drastic changes in the electrostatic interaction between the D2033 residue and crizotinib and reorientation of neighboring residues. In contrast, cabozantinib binding was unaffected by the D2033N substitution, and inhibitory potency against the mutant was retained. Notably, cabozantinib treatment resulted in a rapid clinical and near-complete radiographic response in this patient.
  
  
  
  These results provide the first example of successful therapeutic intervention with targeted therapy to overcome crizotinib resistance in a ROS1-rearranged cancer. Clin Cancer Res; 22(10); 2351-8. ©2015 AACR.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York. drilona@mskcc.org davarem@ohsu.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Romel
authors.initials: R
authors.lastname: Somwar
authors.affiliation: Knight Cancer Institute and Department of Pediatrics, Oregon Health & Science University, Portland, Oregon.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Wagner
authors.affiliation: Huntsman Cancer Institute and Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah.
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Vellore
authors.affiliation: Knight Cancer Institute and Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon. Howard Hughes Medical Institute, Portland, Oregon.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.affiliation: Huntsman Cancer Institute and Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Zabriskie
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jaclyn F
authors.initials: JF
authors.lastname: Hechtman
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Smith
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riely
authors.affiliation: Knight Cancer Institute and Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, Oregon. Howard Hughes Medical Institute, Portland, Oregon.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.affiliation: Huntsman Cancer Institute and Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, Utah.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Knight Cancer Institute and Department of Pediatrics, Oregon Health & Science University, Portland, Oregon. drilona@mskcc.org davarem@ohsu.edu.
authors.forename: Monika A
authors.initials: MA
authors.lastname: Davare
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics; D000077192:Adenocarcinoma of Lung; D000813:Anilides / Q000627:therapeutic use*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D045744:Cell Line, Tumor; D017322:Clinical Trials, Phase II as Topic; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D009857:Oncogenes / Q000187:drug effects / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*
chemical_list: D000813:Anilides; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; C045084:invariant chain; C558660:cabozantinib; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human