title: Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Authors' Affiliations: Departments of Surgery, Radiology, Developmental Biology, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Kim
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cavnar
authors.forename: Noah A
authors.initials: NA
authors.lastname: Cohen
authors.forename: Eric C
authors.initials: EC
authors.lastname: Sorenson
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Greer
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Seifert
authors.forename: Megan H
authors.initials: MH
authors.lastname: Crawley
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Green
authors.forename: Rachel
authors.initials: R
authors.lastname: Popow
authors.forename: Nagavarakishore
authors.initials: N
authors.lastname: Pillarsetty
authors.forename: Darren R
authors.initials: DR
authors.lastname: Veach
authors.forename: Anson T
authors.initials: AT
authors.lastname: Ku
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Rossi
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Dematteo
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D001706:Biopsy; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C000600259:pexidartinib; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016186:Receptor, Macrophage Colony-Stimulating Factor