Characterization of MST1/EGFR inhibition and its efficacy for beta cell protection in diabetes

• Applicant: Kathrin Maedler, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437962465

The loss of functional insulin-producing β-cells is the hallmark of diabetes. Mammalian Sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell failure. Consequently, β-cell deletion of MST1 in mice in vivo or its deficiency in human islets in vitro restores β-cell function, survival and normoglycemia. In addition, MST1 hyper-activation also triggers severe diabetic complications; diabetic cardiomyopathy and nephropathy. Thus, the identification of MST1 inhibitors represents a promising approach for causative diabetes therapy.Through a large biochemical MST1 inhibition screen we identified neratinib, recently FDA approved for breast cancer targeting Her2/EGFR dual kinases, as a potent MST1 inhibitor. Our data show that neratinib improved β-cell survival in vitro under multiple diabetogenic conditions in human islets. In vivo, neratinib restored normoglycemia, as well as β-cell function and mass in a mouse model of diabetes. This project is to establish the combination of MST1/EGFR-Inhibition as novel strategy for the pharmacological intervention to restore functional pancreatic β-cells in type 2 diabetes (T2D) upto a complete in vitro and in vivo characterization. Using several in vitro models of human islets, β-cell lines and diabetes models in vivo, we will characterize underlying cellular mechanisms and molecular mode of action of neratinib as well as of a 1st generation compound with enhanced selectivity for MST1 for characterization as a novel target for β-cell. We will compare them to other previously described inhibitors of EGFR or MST1, and their efficacy for improvement of β-cell survival and function in T2D mouse models. We hypothesize, that the MST1/EGFR combination may have an advantage for the restoration of normoglycemia, as it may also robustly improve insulin sensitivity through EGFR/Her2.

• DFG Programme: Research Grants