Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor Journal Article

Authors: Guo, T.; Agaram, N. P.; Wong, G. C.; Hom, G.; D'adamo, D.; Maki, R. G.; Schwartz, G. K.; Veach, D.; Clarkson, B. D; Singer, S.; DeMatteo, R. P.; Besmer, P.; Antonescu, C. R.
Article Title: Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor
Abstract: Purpose: Resistance is commonly acquired in patients with metastatic gastrointestinal stromal tumor who are treated with imatinibm esylate, often due to the development of secondary mutations in the KIT kinase domain. We sought to investigate the efficacy of second-line tyrosine kinase inhibitors, such as sorafenib, dasatinib, and nilotinib, against the commonly observed imatinib-resistant KIT mutations (KITV654A, KITT670I, KITD820Y, and KITN822K) expressed in the Ba/F3 cellular system. Experimental Design: In vitro drug screening of stable Ba/F3 KIT mutants recapitulating the genotype of imatinib-resistant patients harboring primary and secondary KIT mutations was investigated. Comparison was made to imatinib-sensitive Ba/F3 KIT mutant cells as well as Ba/F3 cells expressing only secondary KIT mutations.The efficacy of drug treatment was evaluated by proliferation and apoptosis assays, in addition to biochemical inhibition of KIT activation. Results: Sorafenib was potent against all imatinib-resistant Ba/F3 KIT double mutants tested, including the gatekeeper secondary mutation KIT WK557-8del/T670I, which was resistant to other kinase inhibitors. Although all three drugs tested decreased cell proliferation and inhibited KIT activation against exon 13 (KITV560del/V654A) and exon 17 (KIT V559D/D820Y) double mutants, nilotinibd id so at lower concentrations. Conclusions: Our results emphasize the need for tailored salvage therapy in imatinib-refractory gastrointestinal stromal tumors according to individual molecular mechanisms of resistance. The Ba/F3 KIT WK557-8del/T670I cells were sensitive only to sorafenibi nhibition, whereas nilotinib was more potent on imatinib-resistant KIT V560del/V654A and KITV559D/D820Y mutant cells than dasatinib and sorafenib. © 2007 American Association for Cancer Research.
Keywords: gene mutation; exon; mutation; sorafenib; drug efficacy; nonhuman; antineoplastic agents; benzenesulfonates; pyridines; cell proliferation; animal cell; mouse; animals; mice; gastrointestinal stromal tumor; imatinib; stem cell factor; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; apoptosis; genotype; drug potency; drug screening; drug resistance, neoplasm; dasatinib; pyrimidines; phosphorylation; protein kinase inhibitors; piperazines; nilotinib; thiazoles; mutant
Journal Title: Clinical Cancer Research
Volume: 13
Issue: 16
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2007-08-15
Start Page: 4874
End Page: 4881
Language: English
DOI: 10.1158/1078-0432.ccr-07-0484
PUBMED: 17699867
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 56" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Gary Schwartz
    384 Schwartz
  2. Ronald P DeMatteo
    635 DeMatteo
  3. David R D'Adamo
    37 D'Adamo
  4. Darren Veach
    76 Veach
  5. Narasimhan P Agaram
    142 Agaram
  6. Cristina R Antonescu
    750 Antonescu
  7. Robert Maki
    215 Maki
  8. Samuel Singer
    270 Singer
  9. Tianhua Guo
    22 Guo
  10. Bayard Clarkson
    199 Clarkson
  11. Peter Besmer
    114 Besmer
  12. Grace C Wong
    11 Wong