A new study has found that dovitinib, a fibroblast growth factor receptor inhibitor, has antitumor efficacy in patient- and cell-line-derived gastrointestinal stromal tumors (GIST). The study, published in Biomedicines, established the xenografts by transplanting human GIST tissue bilaterally in adult female NMRI mice.
“In the clinic, imatinib has revolutionized the treatment of advanced GIST; however, even patients who initially respond to this treatment develop resistance over time, which most commonly is caused by the development of secondary mutations in the KIT gene,” the authors explained. “In GIST cell lines, dovitinib inhibits cell proliferation, although imatinib still appeared to be more potent in cell lines with varying imatinib sensitivity.”
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The research team treated several different mutant mouse models with dovitinib, infigratinib, or binimetinib, a mitogen-activated protein kinase inhibitor, alone or in combination with imatinib. They found that dovitinib treatment resulted in tumor shrinkage, and they attributed the effect to inhibition of KIT, leading to an almost complete halt in proliferation.
Dovitinib was more effective than imatinib in a specific mutant model (KIT exon 9), indicating a potential role for patient selection in the use of this agent in GIST clinical trials. A previous study on this model showed that a standard dose of imatinib did not result in control of tumor growth.
In two other models, KIT exon 11 and 17 mutations, tumor necrosis was induced by dovitinib. The combination of binimetinib and dovitinib had limited additive effects.
Infigratinib alone showed no antitumor effects in the models studied, and its combination with imatinib did not have a better effect than imatinib alone on tumor proliferation inhibition or growth.
Schöffski P, Gebreyohannes Y, Van Looy T, et al. In vivo evaluation of fibroblast growth factor receptor inhibition in mouse xenograft models of gastrointestinal stromal tumor. Biomedicines. Published online May 13, 2022. doi.10.3390/biomedicines10051135