Abstract A32: Targeting RON-mediated metabolic vulnerabilities in recurrent/progressive breast cancer

Abstract

Abstract Despite advances in clinical detection, molecular subtyping, and targeted therapeutics, breast cancer (BC) is the second leading cause of cancer-related death in women. Recurrent and metastatic disease is the underlying cause of BC mortality. Due to fear of recurrence, BC is the most overtreated cancer, creating significant ethical and financial burdens. Through a discovery-based genomics approach, the RON receptor tyrosine kinase was identified as a predictor of BC recurrence. We and others have shown that RON overexpression occurs in more than half of all BCs and that RON levels are a predictor of metastasis and poor survival. Through evaluation of human breast tumor tissue, we provide the first line of evidence that RON overexpression occurs independent of molecular subtype and provide prognostic evidence of RON expression as a biomarker of BC recurrence. Further, we identified glycolysis and cholesterol biosynthesis, two potentially therapeutically targetable processes, as being significantly upregulated by RON. To test the efficacy of reducing cholesterol as a therapy for BC with RON expression, we treated two independent, spontaneous murine breast cancer models with inhibitors directed at RON and/or cholesterol biosynthesis (atorvastatin). Our studies show that either RON or cholesterol inhibition reduced BC progression and that combination treatments blocked progression further. Current studies are under way to determine the mechanisms by which RON promotes metabolic pathway dependency and to directly test in a novel murine model of BC recurrence if targeting these pathways provides a survival benefit. We anticipate that our studies will serve as the scientific underpinnings for rationally designed new combinatorial therapeutic strategies to decrease the morbidity and mortality associated with advanced breast cancer. Citation Format: Brian G. Hunt, Christina A. Wicker, Jennifer Bourn, Elyse Lower, Vinita Takiar, Susan E. Waltz. Targeting RON-mediated metabolic vulnerabilities in recurrent/progressive breast cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A32.