Details

Autor(en) / Beteiligte

• KIM, Teresa S
• CAVNAR, Michael J
• VEACH, Darren R
• KU, Anson T
• ROSSI, Ferdinand
• BESMER, Peter
• ANTONESCU, Cristina R
• SHAN ZENG
• DEMATTEO, Ronald P
• COHEN, Noah A
• SORENSON, Eric C
• GREER, Jonathan B
• SEIFERT, Adrian M
• CRAWLEY, Megan H
• GREEN, Benjamin L
• POPOW, Rachel
• PILLARSETTY, Nagavarakishore

Titel

Increased KIT Inhibition Enhances Therapeutic Efficacy in Gastrointestinal Stromal Tumor

Ist Teil von

• Clinical cancer research, 2014-05, Vol.20 (9), p.2350-2362

Ort / Verlag

Philadelphia, PA: American Association for Cancer Research

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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.