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- W4385459013 abstract "<div>AbstractPurpose:<p>The majority of gastrointestinal stromal tumors (GIST) are driven by constitutively activated KIT/PDGFRA kinases and are susceptible to treatment with tyrosine kinase inhibitors. During treatment, most of these tumors will develop secondary mutations in <i>KIT</i> or <i>PDGFRA</i> inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of IDRX-42, a novel selective KIT inhibitor with high activity toward the most relevant <i>KIT</i> mutations, in 4 GIST xenograft models.</p>Experimental Design:<p>NMRI <i>nu/nu</i> mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (<i>KIT</i>:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (<i>KIT</i>:p.A502_Y503dup), UZLX-GIST25 (<i>KIT</i>:p.K642E), and the cell line–derived model GIST882 (<i>KIT</i>:p.K642E). Mice were treated daily with vehicle (control), imatinib (100 mg/kg), sunitinib (20 mg/kg), avapritinib (5 mg/kg), or IDRX-42 (10 mg/kg, 25 mg/kg). Efficacy was assessed by tumor volume evolution, histopathology, grading of histologic response, and IHC. The Kruskal–Wallis and Wilcoxon matched-pairs tests were used for statistical analysis, with <i>P</i> < 0.05 considered as significant.</p>Results:<p>IDRX-42 (25 mg/kg) caused tumor volume shrinkage in UZLX-GIST25, GIST882, and UZLX-GIST2B, with a relative decrease to 45.6%, 57.3%, and 35.1% on the last day as compared with baseline, and tumor growth delay (160.9%) compared with control in UZLX-GIST9. Compared with controls, IDRX-42 (25 mg/kg) induced a significant decrease in mitosis. In UZLX-GIST25 and GIST882 grade 2–4 histologic response with myxoid degeneration was observed in all IDRX-42 (25 mg/kg)-treated tumors.</p>Conclusions:<p>IDRX-42 showed significant antitumor activity in patient- and cell line–derived GIST xenograft models. The novel kinase inhibitor induced volumetric responses, decreased mitotic activity, and had antiproliferative effects. In models with <i>KIT</i> exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.</p></div>" @default.
- W4385459013 created "2023-08-02" @default.
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- W4385459013 date "2023-08-01" @default.
- W4385459013 modified "2023-10-14" @default.
- W4385459013 title "Data from Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line–Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST)" @default.
- W4385459013 doi "https://doi.org/10.1158/1078-0432.c.6708896.v2" @default.
- W4385459013 hasPublicationYear "2023" @default.
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