Neratinib protects pancreatic beta cells in diabetes

• Published in: Nature communications 2019-11, Vol.10 (1), p.5015-17, Article 5015
• Main Authors: Ardestani, Amin, Li, Sijia, Annamalai, Karthika, Lupse, Blaz, Geravandi, Shirin, Dobrowolski, Aleksandra, Yu, Shan, Zhu, Siying, Baguley, Tyler D., Surakattula, Murali, Oetjen, Janina, Hauberg-Lotte, Lena, Herranz, Raquel, Awal, Sushil, Altenhofen, Delsi, Nguyen-Tran, Van, Joseph, Sean, Schultz, Peter G., Chatterjee, Arnab K., Rogers, Nikki, Tremblay, Matthew S., Shen, Weijun, Maedler, Kathrin
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/109; 13/2; 13/21; 13/89; 14; 49; 49/47; 631/80/304; 64/60; 692/163/2743/137/773; Animal models; Animals; Beta cells; Cell death; Cell Line, Tumor; Cell survival; Cells, Cultured; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Epidermal growth factor receptors; ErbB-2 protein; Humanities and Social Sciences; Humans; Hyperglycemia; Inhibitors; Insulin; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Kinases; Male; Mice, Inbred C57BL; Mice, Obese; multidisciplinary; Pancreas; Protective Agents - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Quinolines - pharmacology; Rats; Science; Science (multidisciplinary); Signal Transduction - drug effects; Signal Transduction - genetics; Streptozocin; Survival
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12880-5

The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Lepr db/db ) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes. Type 1 as well as type 2 diabetes are characterized by a loss of insulin-producing β-cells. Here the authors show that the FDA-approved drug neratinib has beneficial effects on β-cell survival, insulin secretion, and glycemic control in mouse models of diabetes.