Abstract 1499: Combination HIF-2alpha inhibition with cholesterol biosynthesis inhibition decreases colorectal carcinoma growth

Abstract Hypoxic stress in solid tumors promotes cancer cell growth and survival and confers therapeutic resistance. Hypoxia inducible factors (HIFs) are transcription factors that help cells adapt to hypoxic stress. HIFs are often overexpressed in tumors and are associated with worse clinical outcomes. HIF inhibition is a novel therapeutic strategy and belzutifan is a first-in-class HIF-2α inhibitor. Belzutifan has recently been approved for metastatic renal cell carcinoma treatment. However, despite studies showing that HIF-2α is a critical regulator of colorectal carcinoma, belzutifan is not effective in pre-clinical studies of colorectal carcinoma (CRC) growth. HIF-2α inhibition with a small molecule inhibitor, belzutifan, does not affect proliferation of CRC cells (HCT116, SW480) under normoxic or hypoxic conditions. The primary objective of this study was to identify metabolic vulnerabilities in CRC caused by HIF-2α inhibition that can be synergistically targeted to increase cancer cell death. We first performed an unbiased CRISPR screen and identified the cholesterol biosynthesis pathway as a potential target. Inhibiting the cholesterol biosynthesis pathway with HMG-CoA reductase inhibitors, statins, potentiates cell death and reduces in vitro proliferation of HCT116 and SW480 cells when combined with HIF-2α genetic knockdown or HIF-2α inhibition. This effect is dose-dependent in nature and is preserved across the statins class as tested with pitavastatin, simvastatin, and atorvastatin. Planned future studies include in vivo experimentation with autochthonous mouse models of CRC to assess how combination treatment with statin and HIF-2α inhibition affects tumor progression. Ultimately, statins are a widely used, safe, and affordable treatment for atherosclerosis and our data shows that combining statins with belzutifan may be a synergistic therapeutic strategy for CRC. Citation Format: Prarthana Dalal, Boyan Hu, Rashi Singhal, Yatrik Shah. Combination HIF-2alpha inhibition with cholesterol biosynthesis inhibition decreases colorectal carcinoma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1499.