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Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor

Cavnar, M.J.; Kim, T.S.; Cohen, N.A.; Sorenson, E.C.; Greer, J.B.; Seifert, A.M. ; Green, B.L.; Popow, R.; Pillarsetty, N. and Veach, D.R., et al. (2014) In Clinical Cancer Research 20(9).
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 Kit(V558del/+) 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... (More)
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 Kit(V558del/+) 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. (Less)
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type
Contribution to journal
publication status
published
in
Clinical Cancer Research
volume
20
issue
9
publisher
American Association for Cancer Research
external identifiers
  • Scopus:84899708388
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-13-3033
language
English
LU publication?
no
id
3d1c1f27-6858-4936-aef2-75c7e17bc20f
date added to LUP
2016-09-14 10:38:50
date last changed
2016-11-06 04:39:58
@misc{3d1c1f27-6858-4936-aef2-75c7e17bc20f,
  abstract     = {PURPOSE:<br/>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.<br/>EXPERIMENTAL DESIGN:<br/>We treated Kit(V558del/+) 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.<br/>RESULTS:<br/>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.<br/>CONCLUSIONS:<br/>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.},
  author       = {Cavnar, M.J. and Kim, T.S. and Cohen, N.A. and Sorenson, E.C. and Greer, J.B. and Seifert, A.M.  and Green, B.L. and Popow, R. and Pillarsetty, N. and Veach, D.R. and Ku, Anson and Rossi, F. and Besmer, P. and Antonescu, C.R. and Zeng, S. and De Matteo, R.P.},
  issn         = {1078-0432},
  language     = {eng},
  month        = {05},
  number       = {9},
  publisher    = {ARRAY(0x94ad5d8)},
  series       = {Clinical Cancer Research},
  title        = {Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-13-3033},
  volume       = {20},
  year         = {2014},
}