title: Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer.
abstract: OBJECTIVE
  Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1 and ROS1 rearrangements, are complicated by the cost and protracted timeline of drug discovery.
  
  
  METHODS
  In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes.
  
  
  RESULTS
  This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1-transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC50= 9, 26, and 11 nmol/L, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50= 30/170/200 nmol/L, respectively), entrectinib (IC50= 6/2,200/3,500 nmol/L), and PF-06463922 (IC50= 1/270/2 nmol/L). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924 potently inhibited CD74-NTRK1-transformed compared with parental Ba/F3 cells (IC50= 19 nmol/L vs. > 470 nmol/L). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response.
  
  
  CONCLUSIONS
  While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib. Clin Cancer Res; 23(1); 204-13. ©2016 AACR.
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Curtis R
authors.initials: CR
authors.lastname: Chong
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Magda
authors.initials: M
authors.lastname: Bahcall
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.|KU-KIST Graduate School of Converging Science and Technology, Seoul, Republic of Korea.
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.affiliation: Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts, and Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nishino
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Johnson
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu Nathanael_Gray@dfci.harvard.edu.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu Nathanael_Gray@dfci.harvard.edu.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D058990:Molecular Targeted Therapy; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D020917:Receptor, trkA / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; C483813:Ros1 protein, mouse