SOAT1 as a targetable dependency in Pancreatic Adenocarcinoma - ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that is notoriously refractory to treatment. High mortality is driven by late diagnosis, aggressive metastasis, and resistance to both cytotoxic and targeted therapies, making the development of new treatment strategies essential. To interrogate the molecular drivers of aggressive PDAC biology and identify new therapeutic targets, we developed mouse and patient-derived organoid models of progressive disease. In recent work, we leveraged these models to find that the non-essential enzyme SOAT1 (Sterol-O-Acyl transferase 1) is enriched in invasive, metastatic organoids where it promotes the hyperactivation of the mevalonate or cholesterol synthesis pathway. SOAT1 esterifies free cholesterol for storage, disrupting feedback inhibition and leading to increased production of important metabolic byproducts including isoprenoids, which are required for KRAS prenylation, membrane localization, and activation. Genetic ablation of SOAT1 markedly suppressed tumor growth in the transplant setting, designating SOAT1 as a robust therapeutic target in PDAC. SOAT1-deficient PDAC cells also had an impaired ability to migrate, invade, survive and metastasize. Thus, we hypothesize that SOAT1-mediated MVA pathway hyperactivation stimulates multiple pathways that collectively enable the invasion of preneoplastic PanIN cells during disease initiation, and promote the metastasis of established PDAC cells. Here, we will use genetically engineered mouse models to test the effect of Soat1 deletion on PDAC development and metastasis. Further, we will leverage inducible degron models to conduct in-depth characterization of the metabolomic impacts of SOAT1 ablation (Aim 1). Our ultimate goal is to translate these biological findings into new PDAC treatment strategies. To this end, we will use click chemistry and molecular dynamics simulation to develop first-in-class small molecules that function as potent and selective covalent-binding antagonists of SOAT1 (Aim 2). Using orthotopic and metastatic transplants of patient-derived organoids in parallel with autochthonous mouse models, we will comprehensively evaluate the efficacy of lead SOAT1-inhibitory compounds as monotherapy or combination therapeutic agents in the prevention of both early PDAC development and metastasis in vivo (Aim 3). Together, the studies outlined here will provide an exhaustive assessment of the biological role of SOAT1 and the mevalonate pathway across the stages of PDAC development, using both definitive genetic models and pharmacological approaches. These results will define the stage-specific utility of SOAT1 antagonism as an exciting new therapeutic avenue in PDAC, and ultimately yield potent and selective covalent SOAT1 inhibitors that may have direct translational relevance for PDAC treatment.
