Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation Journal Article


Authors: Antonescu, C. R.; Besmer, P.; Guo, T.; Arkun, K.; Hom, G.; Korytowsky, B.; Leversha, M. A.; Jeffrey, P. D.; Desantis, D.; Singer, S.; Brennan, M. F.; Maki, R. G.; DeMatteo, R. P.
Article Title: Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation
Abstract: Most gastrointestinal stromal tumors (GIST) have an activating mutation in either KIT or PDGFRA. Imatinib is a selective tyrosine kinase inhibitor and achieves a partial response or stable disease in about 80% of patients with metastatic GIST. It is now clear that some patients with GIST develop resistance to imatinib during chronic therapy. To identify the mechanism of resistance, we studied 31 patients with GIST who were treated with imatinib and then underwent surgical resection. There were 13 patients who were nonresistant to imatinib, 3 with primary resistance, and 15 with acquired resistance after initial benefit from the drug. There were no secondary mutations in KIT or PDGFRA in the nonresistant or primary resistance groups. In contrast, secondary mutations were found in 7 of 15 (46%) patients with acquired resistance, each of whom had a primary mutation in KIT exon 11. Most secondary mutations were located in KIT exon 17. KIT phosphorylation was heterogeneous and did not correlate with clinical response to imatinib or mutation status. That acquired resistance to imatinib in GIST commonly occurs via secondary gene mutation in the KIT kinase domain has implications for strategies to delay or prevent imatinib resistance and to employ newer targeted therapies. © 2005 American Association for Cancer Research.
Keywords: adult; clinical article; human tissue; protein phosphorylation; treatment outcome; aged; aged, 80 and over; middle aged; gene mutation; exon; mutation; disease course; antineoplastic agents; drug targeting; protein domain; gastrointestinal stromal tumor; imatinib; stem cell factor; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; receptor, platelet-derived growth factor alpha; enzyme inhibition; genotype; drug resistance, neoplasm; protein tyrosine kinase; pyrimidines; cancer resistance; protein tyrosine kinase inhibitor; blotting, western; correlation analysis; amino acid sequence; molecular sequence data; drug mechanism; long term care; protein-tyrosine kinases; piperazines; dna mutational analysis; platelet derived growth factor a
Journal Title: Clinical Cancer Research
Volume: 11
Issue: 11
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2005-06-01
Start Page: 4182
End Page: 4190
Language: English
DOI: 10.1158/1078-0432.ccr-04-2245
PUBMED: 15930355
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 305" - "Export Date: 24 October 2012" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Murray F Brennan
    755 Brennan
  2. Ronald P DeMatteo
    596 DeMatteo
  3. Philip D Jeffrey
    30 Jeffrey
  4. Cristina R Antonescu
    606 Antonescu
  5. Robert Maki
    210 Maki
  6. Samuel Singer
    225 Singer
  7. Tianhua Guo
    22 Guo
  8. Peter Besmer
    80 Besmer
  9. Knarik Arkun
    8 Arkun