title: Acquired Resistance to Crizotinib in NSCLC with MET Exon 14 Skipping.
abstract: MET proto-oncogene, receptor tyrosine kinase gene (MET) exon 14 skipping is a targetable alteration in lung cancer. Treatment with MET proto-oncogene, receptor tyrosine kinase inhibitor can cause dramatic responses in patients whose cancers have MET exon 14 skipping. Little is known, however, about acquired resistance in patients with MET exon 14 skipping.
  
  
  
  Biopsy specimens obtained at baseline and at the time of progression for a patient being treated with crizotinib were compared using targeted next-generation sequencing to assess for mechanisms of resistance.
  
  
  
  An acquired mutation in the MET kinase domain, D1228N, was found at time of progression on crizotinib in a patient with MET exon 14 skipping.
  
  
  
  One potential mechanism of acquired resistance to crizotinib in patients with MET exon 14 skipping is through second-site mutations in the MET gene. Understanding mechanisms of resistance will be important in optimizing therapy in these patients.
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: rheist@partners.org.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Darrell
authors.initials: D
authors.lastname: Borger
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Arellano
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Long P
authors.initials: LP
authors.lastname: Le
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
mesh_terms: D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*
chemical_list: C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D019859:Proto-Oncogene Proteins c-met
keywords: Acquired resistance; MET exon 14 skipping; NSCLC; Targeted therapy