Abstract 2992: Uncovering metabolic dysregulation and therapeutic targets in aneuploid models of squamous cell carcinoma

Abstract Squamous cell carcinomas (SCCs) arise from epithelial tissues in the lung, head and neck, esophagus, bladder, and cervix. SCCs lack canonical oncogenic mutations and urgently need targeted therapies. Aneuploidy—chromosomal losses or gains, is rare and poorly tolerated in normal cells but occurs in 90% of tumors in tissue-specific patterns. SCCs are characterized by near-universal early chromosome 3p deletion and 3q gain, which correlate with poor prognosis and metastasis. To study effects of 3p deletion in human cells, we used CRISPR-Cas9 to delete a copy of 3p in human immortalized lung epithelial cells, representing the basal cell (lung SCC cell-of-origin). In a subset of clones with 3p deletion, we observed whole chromosome duplication of the unaltered chromosome 3 copy. As a result, these cells transitioned to a state of 3q gain, providing us models for 3p loss, 3q gain, and 3 disomy. To uncover vulnerabilities associated with chromosome 3 arm aneuploidies, we performed drug-repurposing and CRISPRi screens in our engineered cells. In 3q gain cells, the top genetic hit was sterol regulatory element-binding factor 1 (SREBF1), a key regulator of cholesterol and fatty acid biosynthesis. Compared to cells without 3q gain, 3q gain cells were more sensitive to knockdown of SREBF1, co-factor SCAP, and downstream target HMG-CoA reductase (HMGCR), the rate-limiting enzyme in cholesterol synthesis. HMGCR inhibitors (several statins, including mevastatin) were top chemical hits, inducing higher cell death in 3q gain cells. Chemical inhibition of SREBF1 using fatostatin recapitulated effects seen with genetic knockdown. Rescue with mevalonate or geranylgeranyl pyrophosphate (GGPP, a product of the mevalonate pathway involved in protein prenylation) demonstrated the toxicity of pathway inhibition are on-target. Transcriptomic and lipidomic profiling suggest that increased statin sensitivity of 3q gain cells is due to their reduced activation of SREBF1 and HMGCR, causing increased cell death upon inhibition of the mevalonate pathway. Ongoing mechanistic studies will investigate how aneuploidy alters lipid metabolism and contributes to cancer. Statins have been shown to induce tumor-specific apoptosis and reduce cancer risk, though these effects can be highly variable and context-dependent. Preliminary studies in organoid cultures and SCC cancer cell lines suggest that 3q gain is a biomarker of statin response and sensitivity in SCCs. Mevastatin and fatostatin co-treatment, inhibition at two points in the mevalonate pathway, showed synergy, suggesting statin potentiation that could be beneficial in cancer therapy. Additionally, 3q gain cells showed increased toxicity in response to other cholesterol-lowering compounds. Understanding aneuploidy-induced vulnerabilities will reveal how aneuploidies promote tumorigenesis and help identify precision medicine targets for SCCs with 3q gain. Citation Format: Nadja Zhakula, Sejal Jain, Laura Byron, Joan J. Castellano, Matthew L. Meyerson, Alison M. Taylor. Uncovering metabolic dysregulation and therapeutic targets in aneuploid models of squamous cell carcinoma [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 2992.