title: Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.
abstract: OBJECTIVE
  ROS1 rearrangement leads to constitutive ROS1 activation with potent transforming activity. In an ongoing phase I trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib shows remarkable initial responses in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusions; however, cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in ROS1. Thus, understanding the crizotinib-resistance mechanisms in ROS1-rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required.
  
  
  METHODS
  The sensitivity of CD74-ROS1-transformed Ba/F3 cells to multiple ALK inhibitors was examined. Acquired ROS1 inhibitor-resistant mutations in CD74-ROS1 fusion were screened by N-ethyl-N-nitrosourea mutagenesis with Ba/F3 cells. To overcome the resistance mutation, we performed high-throughput drug screening with small-molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials. The effect of the identified drug was assessed in the CD74-ROS1-mutant Ba/F3 cells and crizotinib-resistant patient-derived cancer cells (MGH047) harboring G2032R-mutated CD74-ROS1.
  
  
  RESULTS
  We identified multiple novel crizotinib-resistance mutations in the ROS1 kinase domain, including the G2032R mutation. As the result of high-throughput drug screening, we found that the cMET/RET/VEGFR inhibitor cabozantinib (XL184) effectively inhibited the survival of CD74-ROS1 wild-type (WT) and resistant mutants harboring Ba/F3 and MGH047 cells. Furthermore, cabozantinib could overcome all the resistance by all newly identified secondary mutations.
  
  
  CONCLUSIONS
  We developed a comprehensive model of acquired resistance to ROS1 inhibitors in NSCLC with ROS1 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance.
authors.affiliation: Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.affiliation: Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Lockerman
authors.affiliation: Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Sumie
authors.initials: S
authors.lastname: Koike
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.affiliation: Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. Department of Medical Genome Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan. naoya.fujita@jfcr.or.jp.
authors.forename: Naoya
authors.initials: N
authors.lastname: Fujita
mesh_terms: D000813:Anilides / Q000008:administration & dosage*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage*
chemical_list: D000813:Anilides; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; C045084:invariant chain; C558660:cabozantinib; D000077547:Crizotinib; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human