title: Tyrosine kinase inhibitors in the treatment of unresectable or metastatic gastrointestinal stromal tumors.
abstract: BACKGROUND
  Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Proliferation of GIST is driven by activating mutations in the KIT or PDGFRA genes that found in most sporadic GISTs. Surgery is the main remedial measure for primary GIST, and imatinib is the principal therapeutic of choice for unresectable or metastatic GIST. Imatinib revolutionized treatment for unresectable or metastatic GISTs; however, resistance to imatinib has inevitably developed for most GIST patients.
  
  
  METHODS
  PubMed was searched to find biological studies of GIST and clinical trials of molecularly targeted agents on unresectable or metastatic GISTs, and the key papers found have been reviewed. In this paper, the standard therapy which includes imatinib, sunitinib and regorafenib for unresectable or metastatic GIST has been reviewed and molecular mechanisms of resistance for tyrosine kinase inhibitors (TKIs) have been postulated and discussed. Treatment measures for resistant GIST and therapeutic choices after the standard therapy have also been described.
  
  
  CONCLUSIONS
  The standard therapy for unresectable or metastatic GISTs is first-line imatinib, second-line sunitinib and third-line regorafenib. After standard therapy, best supportive care or clinical trials is recommended in the guidelines. However, patients may benefit from continuation of TKIs beyond disease progression and from rechallenge of TKIs used previously.
authors.affiliation: National Cancer Center Hospital East, Surgery , 6-5-1 Kashiwanoha, Kashiwa, 277-8577 , Japan.
authors.forename: Toshirou
authors.initials: T
authors.lastname: Nishida
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Naito
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000008:administration & dosage; D009154:Mutation; D009362:Neoplasm Metastasis; D010671:Phenylurea Compounds / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D000077210:Sunitinib
chemical_list: D001549:Benzamides; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C559147:regorafenib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000077210:Sunitinib
keywords: imatinib; molecularly targeted therapy; regorafenib; resistance; sunitinib; tyrosine kinase inhibitor