title: KIT and BRAF heterogeneous mutations in gastrointestinal stromal tumors after secondary imatinib resistance.
abstract: OBJECTIVE
  Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the digestive tract and characterized by expression of KIT protein. Imatinib is the frontline therapy for metastatic and unresectable GIST patients showing clinical responses in 80 % of cases. Despite the often long-lasting clinical benefit seen in most patients treated with imatinib, many will eventually suffer disease progression. The most frequent mechanism of imatinib resistance in GIST is the acquisition of secondary mutations in either KIT or PDGFRA. There are also some imatinib-resistant GIST patients lacking an identifiable mechanism of treatment failure. Recently, activating BRAF mutation was detected in a small percentage of GISTs. In this study, we report a case of GIST with acquired resistance to imatinib during therapy.
  
  
  METHODS
  Histological, immunohistochemical, Western blot and mutational analyses were performed on GIST tissues before and after imatinib resistance.
  
  
  RESULTS
  The imatinib-resistant tumor showed not only heterogeneous mutations of KIT and BRAF besides the primary mutation, but also transdifferentiation into a rhabdomyosarcoma phenotype. According to Western blot analysis, in imatinib-resistant GIST with both KIT V559D and BRAF V600E mutations, the inhibition of KIT V559D by imatinib caused a strong decrease of AKT phosphorylation, while ERK1/2 phosphorylation was not affected.
  
  
  CONCLUSIONS
  This finding, in combination with the loss of KIT expression, suggests the possibility of activation of RAS-RAF-MEK-ERK pathways driven by a KIT-independent oncogenic mechanism. Understanding the genetic aberrations beyond KIT and PDGFRA may lead to the identification of additional therapeutic targets for GISTs.
authors.affiliation: Department of Oncology, Hangzhou Cancer Hospital, The First People's Hospital of Hangzhou, Hangzhou, 310006, China. tztree@126.com.
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Emergency, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
authors.forename: Ke-er
authors.initials: KE
authors.lastname: Huang
authors.affiliation: Department of Oncology, Hangzhou Cancer Hospital, The First People's Hospital of Hangzhou, Hangzhou, 310006, China.
authors.forename: Yue-long
authors.initials: YL
authors.lastname: Pan
authors.affiliation: Department of Oncology, Hangzhou Cancer Hospital, The First People's Hospital of Hangzhou, Hangzhou, 310006, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Hangzhou Cancer Hospital, The First People's Hospital of Hangzhou, Hangzhou, 310006, China.
authors.forename: Song-dan
authors.initials: SD
authors.lastname: Pan
authors.affiliation: Department of Oncology, Hangzhou Cancer Hospital, The First People's Hospital of Hangzhou, Hangzhou, 310006, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Zhejiang Academy of Medical Sciences, Hangzhou, 310003, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jia
authors.affiliation: Zhejiang Academy of Medical Sciences, Hangzhou, 310003, China.
authors.forename: Xiao-liang
authors.initials: XL
authors.lastname: Zheng
authors.affiliation: Department of Oncology, Taizhou Hospital of Zhejiang Province, Taizhou, 317700, China.
authors.forename: De-you
authors.initials: DY
authors.lastname: Tao
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D054338:Cell Transdifferentiation / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D007150:Immunohistochemistry; D008297:Male; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; Gastrointestinal stromal tumor; Imatinib resistance; KIT; Rhabdomyosarcomatous differentiation