Abstract 2300: Insulin receptor kinase inhibition is better tolerated than hypoinsulinemia and more effective than metformin in treating breast cancer

Abstract

Abstract Epidemiologic and experimental evidence suggest that a subset of breast cancer is insulin-responsive, but it is unclear if safe and effective therapies that target the insulin receptor can be developed. We demonstrate that both insulin receptor family tyrosine kinase inhibition and insulin deficiency have anti-neoplastic activity in a model of insulin-responsive breast cancer in mice metabolically normal at baseline. In contrast to insulin deficiency, insulin receptor inhibition does not lead to hyperglycemia and is well-tolerated. We show that pharmacokinetic factors explain the safety of receptor inhibition relative to ligand deficiency, as BMS-536924 does not accumulate in muscle at levels sufficient to block insulin-stimulated glucose uptake. Metformin, which lowers the elevated insulin levels present in settings of insulin resistance, had minimal activity in this model. The findings highlight the importance of tissue-specific drug accumulation as a determinant of efficacy and toxicity of tyrosine kinase inhibitors, and suggest that therapeutic targeting of the insulin receptor family for cancer treatment is practical. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2300. doi:10.1158/1538-7445.AM2011-2300