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|Authors||Luna De Sutter; Agnieszka Wozniak; Jasper Verreet; Ulla Vanleeuw; Lore De Cock; Nina Linde; Christine Drechsler; Christina Esdar; Raf Sciot; Patrick Schoffski|
|Title||Anti-tumor effects of the novel KIT mutant inhibitor M4205 in patient-derived gastrointestinal stromal tumor (GIST) xenograft models|
|Abstract Text||Background: The majority of GISTs are driven by constitutively activated KIT/PDGFRA kinases and susceptible to treatment with tyrosine kinase inhibitors such as imatinib, sunitinib and regorafenib. During treatment most tumors will develop heterogeneous secondary mutations in KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of M4205, a novel specific KIT inhibitor with high activity towards the most relevant KIT mutations, in patient-derived GIST xenograft models. Methods: NMRI nu/nu mice (n=146) were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G) known to be resistant to both imatinib and sunitinib, with the dose-dependent imatinib-sensitive and sunitinib-sensitive models 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 (100mg/kg), avapritinib (5mg/kg), sunitinib (20mg/kg), or M4205 (10mg/kg, 25mg/kg). Efficacy was assessed by tumor volume evolution, histopathology [hematoxilin & eosine staining (H&E)] and immunohistochemistry [Ki-67, phospho-Histone H3 (pHH3), cleaved PARP]. Histologic response (HR) was graded as previously described°. Mann Whitney U and Wilcoxon Matched Pairs tests were used for statistical analysis, with p<0.05 considered as significant. Results: M4205 (25mg/kg) caused tumor volume shrinkage in UZLX-GIST2B, -GIST25 and GIST882 with relative decrease to 45.6%, 35.1% and 57.3% on the last day as compared to baseline. In UZLX-GIST9 tumor growth to 132.4% was observed in M4205 (25mg/kg)-treated tumors as compared to baseline. In all models we observed significant smaller tumor volumes in M4205 (25mg/kg)-treated tumors compared to control, and this antitumor activity was superior to imatinib in UZLX-GIST9, -GIST2B and GIST882, and to sunitinib in -GIST25. Compared to controls, M4205 (25mg/kg) induced a significant decrease in mitosis (H&E) in all models, confirmed on pHH3 and Ki-67 immunostainings in three models. In -GIST25 and GIST882 grade 2-4 HR with myxoid degeneration was observed in all tumors. All treatments were well tolerated. Conclusion: M4205 has significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induces volumetric responses, decreases mitotic activity, has antiproliferative effects and in models with KIT exon 13 mutation leads to characteristic myxoid degeneration. * Cornillie et al. Mol Cancer Ther 2019; 18(6):1168-1178 ° Agaram et al. Clin Cancer Res 2007; 13:170-81|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|IDRX-42||M-4205|M 4205|M4205|IDRX 42|IDRX42||KIT Inhibitor 57||IDRX-42 is a specific KIT inhibitor, which potentially decreases mitosis and tumor cell growth (Cancer Res 2022;82(12_Suppl):Abstract nr 2666).|
|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 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 (Cancer Res 2022;82(12_Suppl):Abstract nr 2666).||detail...|
|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 (Cancer Res 2022;82(12_Suppl):Abstract nr 2666).||detail...|
|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 (Cancer Res 2022;82(12_Suppl):Abstract nr 2666).||detail...|