Abstract 5873: ERα coordinates with squalene synthase to confer statin resistance in lung cancer

Abstract Statins are widely used to treat hypercholesterolemia by inhibiting hydroxymethylglutaryl coenzyme A reductase (HMGCR). Accumulating evidence suggests that statins also have protective effects against cancer recurrence. However, the role of statins in preventing lung cancer and biomarkers for predicting statin treatment response remains lacking. This study analyzes molecular features that dictate statin sensitivity in lung cancer by correlating large-scale statin sensitivity data and basal gene expression in a collection of 125 lung cancer patients. We identified a gene signature associated with lovastatin sensitivity and showed that gene expression in mesenchymal molecular features, the cholesterol biosynthesis pathway, and estrogen receptor alpha (ERα) signaling were key determinants of lovastatin sensitivity in lung cancer cells. To this end, we further discovered that overexpression of a committed step enzyme in cholesterol biosynthesis farnesyl-diphosphate farnesyltransferase 1 (FDFT1), also known as squalene synthase (SQS), is capable of activating ERα and is associated with increased statin tolerance. In clinical specimens, overexpression of SQS positively correlated with nuclear expression of ERα in lung cancer patients, and the combination of SQS and ERα is a powerful prognostic predictor for lung cancer. Activation of the SQS-ERα signaling axis and epithelial-to-mesenchymal transition (EMT) status represents two important features in determining statin sensitivity in lung cancer. Keywords: Statin, cholesterol biosynthesis, squalene synthase, estrogen receptor α, Epithelial-mesenchymal transition Citation Format: Yi-Fang Yang. ERα coordinates with squalene synthase to confer statin resistance in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5873.