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.