Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor Journal Article

Authors: Kim, T. S.; Cavnar, M. J.; Cohen, N. A.; Sorenson, E. C.; Greer, J. B.; Seifert, A. M.; Crawley, M. H.; Green, B. L.; Popow, R.; Pillarsetty, N.; Veach, D. R.; Ku, A. T.; Rossi, F.; Besmer, P.; Antonescu, C. R.; Zeng, S.; De Matteo, R. P.
Article Title: Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor
Abstract: Purpose: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and a model of targeted molecular therapy. GIST depends on oncogenic KIT signaling and responds to the tyrosine kinase inhibitor imatinib. However, imatinib is rarely curative. We hypothesized that PLX3397, which inhibits KIT and colony-stimulating-factor-1 receptor (CSF1R), would be more efficacious than imatinib in GIST by also depleting tumor-associated macrophages, which are generally thought to support tumor growth. Experimental Design: We treated KitV558del/+ mice that develop GIST or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed. Results: PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit V558del/+ murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding CSF1R inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules. Conclusions: PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication. © 2014 AACR.
Journal Title: Clinical Cancer Research
Volume: 20
Issue: 9
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2014-05-01
Start Page: 2350
End Page: 2362
Language: English
DOI: 10.1158/1078-0432.ccr-13-3033
PROVIDER: scopus
PMCID: PMC4008656
PUBMED: 24583793
Notes: Clin. Cancer Res. -- Export Date: 2 June 2014 -- CODEN: CCREF -- Source: Scopus
Citation Impact
MSK Authors
  1. Ronald P DeMatteo
    636 DeMatteo
  2. Darren Veach
    81 Veach
  3. Cristina R Antonescu
    790 Antonescu
  4. Michael Joseph Cavnar
    30 Cavnar
  5. Ferdinando Rossi
    23 Rossi
  6. Shan Zeng
    26 Zeng
  7. Peter Besmer
    115 Besmer
  8. Jonathan Bruce Greer
    13 Greer
  9. Teresa Sora Kim
    23 Kim
  10. Rachel Popow
    9 Popow
  11. Megan Hannon Crawley
    12 Crawley
  12. Benjamin Lawrence Green
    10 Green
  13. Noah Avram Cohen
    19 Cohen
  14. Adrian Marcel Seifert
    16 Seifert
  15. Anson Tai Ku
    6 Ku