ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
37 citing papers in PubMed, 52 citations in OpenAlex.
- Trial
- c-KIT joins the TSC ToolKIT: a new driver of renal cystogenesis.EMBO molecular medicine · 2026Article
- The critical role of the proto-oncogene c-Kit in TSC renal cystogenesis.EMBO molecular medicine · 2026Article
- Transient CSF1R inhibition ameliorates behavioral deficits in Cntnap2 knockout and valproic acid-exposed mouse models of autism.Journal of neuroinflammation · 2024Article
- KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST.Cell communication and signaling : CCS · 2024Review
- Article
- Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers.Molecular cancer · 2023Review
- 3-Alkenyl-2-oxindoles: Synthesis, antiproliferative and antiviral properties against SARS-CoV-2.Bioorganic chemistry · 2021Article
- Oncogenic KIT Modulates Type I IFN-Mediated Antitumor Immunity in GIST.Cancer immunology research · 2021Article
- Type and Gene Location ofCancers · 2021Article
- The management of metastatic GIST: current standard and investigational therapeutics.Journal of hematology & oncology · 2021Review
- The V654A second-site KIT mutation increases tumor oncogenesis and STAT activation in a mouse model of gastrointestinal stromal tumor.Oncogene · 2020Article
- The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy.Acta pharmaceutica Sinica. B · 2020Review
- A Phase I Study of Binimetinib (MEK162) Combined with Pexidartinib (PLX3397) in Patients with Advanced Gastrointestinal Stromal Tumor.The oncologist · 2019Article
- Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo.Experimental neurology · 2019Article
- Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms.The Journal of clinical investigation · 2019Article
- Microglia prevent peripheral immune cell invasion and promote an anti-inflammatory environment in the brain of APP-PS1 transgenic mice.Journal of neuroinflammation · 2018Article
- Macrophages and CD8Cancer immunology research · 2018Article
- Tumor-Associated Macrophages as Target for Antitumor Therapy.Archivum immunologiae et therapiae experimentalis · 2018Review
Corrections and comments
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Authors and funding
17 authors at 1 institution in 1 country.
Funding
Abstract
purposeGastrointestinal 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
designWe 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.
resultsPLX3397 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.
conclusionsPLX3397 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.