TY - JOUR
T1 - Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor
AU - Kim, Teresa S.
AU - Cavnar, Michael J.
AU - Cohen, Noah A.
AU - Sorenson, Eric C.
AU - Greer, Jonathan B.
AU - Seifert, Adrian M.
AU - Crawley, Megan H.
AU - Green, Benjamin L.
AU - Popow, Rachel
AU - Pillarsetty, Nagavarakishore
AU - Veach, Darren R.
AU - Ku, Anson T.
AU - Rossi, Ferdinand
AU - Besmer, Peter
AU - Antonescu, Cristina R.
AU - Zeng, Shan
AU - De Matteo, Ronald P.
PY - 2014/5/1
Y1 - 2014/5/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-13-3033
DO - 10.1158/1078-0432.CCR-13-3033
M3 - Article
C2 - 24583793
AN - SCOPUS:84899708388
SN - 1078-0432
VL - 20
SP - 2350
EP - 2362
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -