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Ref Type Journal Article
PMID (37223931)
Authors De Sutter L, Wozniak A, Verreet J, Vanleeuw U, De Cock L, Linde N, Drechsler C, Esdar C, Sciot R, Schöffski P
Title Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line-Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST).
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 29 15 2023 Aug 01 2859-2868 Clin Cancer Res
URL
Abstract Text 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 KIT or PDGFRA 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 KIT mutations, in 4 GIST xenograft models.NMRI nu/nu mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT:p.K642E), and the cell line-derived model GIST882 (KIT: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 P < 0.05 considered as significant.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.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 KIT exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.

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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 K642E gastrointestinal stromal tumor predicted - sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 treatment inhibited mitosis and decreased tumor growth in a cell line xenograft model and a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT K642E (PMID: 37223931). 37223931
KIT W557Lfs*5 KIT P577del KIT D820G gastrointestinal stromal tumor predicted - sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 treatment inhibited mitosis and decreased tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT P577del, W557Lfs*5, and D820G (PMID: 37223931). 37223931
KIT A502_Y503dup gastrointestinal stromal tumor predicted - sensitive IDRX-42 Preclinical - Pdx Actionable In a preclinical study, IDRX-42 treatment inhibited mitosis and decreased tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT A502_Y503dup (PMID: 37223931). 37223931