American Association for Cancer Research
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Supplementary Figure S11-6 from Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models

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posted on 2024-02-01, 08:41 authored by Manja Friese-Hamim, Maria J. Ortiz Ruiz, Olga Bogatyrova, Marina Keil, Felix Rohdich, Beatrix Blume, Birgitta Leuthner, Frank Czauderna, Diane Hahn, Julia Jabs, Frank Jaehrling, Timo Heinrich, Roland Kellner, Katherine Chan, Amy H.Y. Tong, Dirk Wienke, Jason Moffat, Andree Blaukat, Frank T. Zenke

Body weight curves for RCC PDX model RXF-2717-bearing mice treated with vehicle, M8891 (100 mg/kg, daily, per os), cabozantinib (10 mg/kg, daily, per os), or the combination are shown

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Merck KGaA (Merck)

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ARTICLE ABSTRACT

N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small-molecule inhibitor blocking the growth of human endothelial cells and differentially inhibiting cancer cell growth. A CRISPR genome-wide screen identified the tumor suppressor p53 and MetAP1/MetAP2 as determinants of resistance and sensitivity to pharmacologic MetAP2 inhibition. A newly identified substrate of MetAP2, translation elongation factor 1-alpha-1 (EF1a-1), served as a pharmacodynamic biomarker to follow target inhibition in cell and mouse studies. Robust angiogenesis and tumor growth inhibition was observed with M8891 monotherapy. In combination with VEGF receptor inhibitors, tumor stasis and regression occurred in patient-derived xenograft renal cell carcinoma models, particularly those that were p53 wild-type, had Von Hippel-Landau gene (VHL) loss-of-function mutations, and a mid/high MetAP1/2 expression score.