title: RET inhibition: implications in cancer therapy.
abstract: BACKGROUND
  The RET gene encodes a receptor tyrosine kinase essential for ontogenesis of the enteric nervous system and kidney. Following identification of RET, it was found that somatic rearrangements of this gene, conventionally designated as RET/PTC, are frequently present in papillary thyroid carcinoma. Subsequently, activating germ line point mutations of RET were identified as being responsible for the hereditary medullary thyroid carcinoma syndromes MEN2A, MEN2B and FMTC. RET rearrangements have recently been identified in a small fraction of lung adenocarcinomas.
  
  
  METHODS
  The authors review the current field concerning the RET gene and protein, its involvement in cancer and the preclinical and clinical studies which highlight its role as a potentially important therapeutic target for several cancers.
  
  
  CONCLUSIONS
  Many multitargeted inhibitors which crossreact with RET have been developed and investigated in clinical trials targeting many cancer indications. In particular, VEGFR/PDGFR inhibitors, widely explored as antiangiogenics, have been intensively studied in thyroid carcinoma patients. Notwithstanding the efficacy observed with such agents, their common clinical activity in thyroid carcinoma is of short duration and includes frequent and severe side effects, limiting their therapeutic action. These findings are discussed and the need for improved, more specific RET-targeting drugs is highlighted.
authors: UO Molecular Mechanisms, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via GA. Amadeo, 42-20133 Milano, Italy. mariagrazia.borrello@istitutotumori.mi.it
authors: Maria Grazia
authors: MG
authors: Borrello
authors: Elena
authors: E
authors: Ardini
authors: Laura D
authors: LD
authors: Locati
authors: Angela
authors: A
authors: Greco
authors: Lisa
authors: L
authors: Licitra
authors: Marco A
authors: MA
authors: Pierotti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human