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Ref Type Journal Article
PMID (35625872)
Authors Schöffski P, Gebreyohannes Y, Van Looy T, Manley P, Growney JD, Squires M, Wozniak A
Title In Vivo Evaluation of Fibroblast Growth Factor Receptor Inhibition in Mouse Xenograft Models of Gastrointestinal Stromal Tumor.
Journal Vol Issue Date Pages Journal Short Title
Biomedicines 10 5 2022 May 13 Biomedicines
URL
Abstract Text Advanced gastrointestinal stromal tumors (GIST) are typically treated with tyrosine kinase inhibitors, and imatinib is the most commonly used standard of care in first line treatments. The use of this and other tyrosine kinase inhibitors is associated with objective tumor responses and prolongation of progression-free and overall survival, but the treatment of metastatic disease is non-curative due to the selection or acquisition of secondary mutations and the activation of alternative kinase signaling pathways, leading to resistance and disease progression after an initial response. The present preclinical study evaluated the potential use of the fibroblast growth factor receptor inhibitors infigratinib and dovitinib alone or in combination with the mitogen-activated protein kinase inhibitor binimetinib in mouse models of GIST with different sensitivity or resistance to imatinib. Patient- and cell-line-derived GIST xenografts were established by bilateral, subcutaneous transplantation of human GIST tissue in female adult nu/nu NMRI mice. The mice were treated with dovitinib, infigratinib, or binimetinib, either alone or in combination with imatinib. The safety of treated animals was assessed by well-being inspection and body weight measurement. Antitumor effects were assessed by caliper-based tumor measurement. H&E staining and immunohistochemistry were used for assessing anti-mitotic and pro-apoptotic activity of the experimental treatments. Western blotting was used for assessing effects of the agents on kinase signaling pathways. Anti-angiogenic activity was assessed by measuring tumor vessel density. Dovitinib was found to have antitumor efficacy in GIST xenografts characterized by different imatinib resistance patterns. Dovitinib had better efficacy than imatinib (both at standard and increased dose) and was found to be well tolerated. Dovitinib had better efficacy in a KIT exon 9 mutant model, highlighting a role of patient selection in clinical GIST trials with the agent. In a model with KIT exon 11 and 17 mutations, dovitinib induced tumor necrosis, most likely due to anti-angiogenic effects. Additive effects combining dovitinib with binimetinib were limited.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT A502_Y503dup gastrointestinal stromal tumor predicted - sensitive Binimetinib + Dovitinib Preclinical - Pdx Actionable In preclinical study, combination treatment with Mektovi (binimetinib) and Dovitinib (TKI258) resulted in tumor shrinkage in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT A502_Y503dup (PMID: 35625872). 35625872
KIT W557Lfs*5 KIT P577del KIT D820G gastrointestinal stromal tumor predicted - sensitive Dovitinib Preclinical - Pdx Actionable In preclinical study, Dovitinib (TKI258) treatment stabilized tumor volume in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT P577del, KIT W557Lfs*5, and KIT D820G (PMID: 35625872). 35625872
KIT A502_Y503dup gastrointestinal stromal tumor predicted - sensitive Dovitinib Preclinical - Pdx Actionable In preclinical study, Dovitinib (TKI258) treatment resulted in tumor shrinkage in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT A502_Y503dup (PMID: 35625872). 35625872
KIT V560D KIT D820A gastrointestinal stromal tumor predicted - sensitive Imatinib + Infigratinib Preclinical - Cell line xenograft Actionable In a preclinical study, combination treatment with Gleevec (imatinib) and Truseltiq (infigratinib) treatment resulted in tumor shrinkage in a gastrointestinal stromal tumor cell line xenograft model harboring KIT V560D and KIT D820A (PMID: 35625872). 35625872
KIT A502_Y503dup gastrointestinal stromal tumor conflicting Imatinib Preclinical - Pdx Actionable In a preclinical study, Gleevec (imatinib) treatment stabilized tumor growth in a gastrointestinal stromal tumor patient-derived xenograft (PDX) model harboring KIT A502_Y503dup (PMID: 35625872). 35625872