# Fatty Acid Synthase as a Potential Metabolic Vulnerability in Ocular Adnexal Sebaceous Carcinoma

## TL;DR

This study shows that blocking fatty acid synthase could be a new treatment approach for a rare and aggressive eyelid cancer.

## Contribution

The study identifies fatty acid synthase as a metabolic vulnerability in ocular adnexal sebaceous carcinoma.

## Key findings

- Fatty acid synthase inhibition reduced tumor cell viability and triggered apoptosis.
- MYC overexpression and fatty acid synthase activity are linked in driving tumor progression.
- Fatty acid saturation profiles changed significantly with fatty acid synthase inhibition.

## Abstract

This study aimed to better understand ocular adnexal sebaceous carcinoma, a rare and aggressive cancer of the eyelid that currently has no targeted treatments. Using cultured tumor cells and a genetically modified mouse model, we determined that this cancer may be vulnerable to alterations in the fat synthesizing enzyme fatty acid synthase. Fatty acid synthase and the gene MYC work together to change how the tumor cells make and use fats, which are important for tumor progression. By blocking fatty acid synthase, cell growth was slowed, and cell death was triggered, uncovering a potential weakness in the cancer’s metabolism. These findings open the door to developing new therapies that could improve outcomes for patients facing this potentially fatal condition.

Background: MYC dysregulation is frequent in ocular adnexal sebaceous carcinoma (SebCA), an aggressive malignancy without precision therapy. Fatty acid synthase (FASN) expression and lipid metabolism are commonly perturbed in high-MYC-expressing tumors; however, the role of MYC and FASN in the coregulation of lipid biosynthesis and tumorigenesis in SebCA is unknown. Methods: The aim of this study was to characterize the effects of FASN inhibition on MYC expression, oncogenic processes, and lipid profiles in vitro, using non-neoplastic human Meibomian gland epithelial cells (HMGECs) and three primary SebCA cell lines, and in vivo, utilizing a conditionally MYC-overexpressing mouse model. Results: FASN inhibition reduced cell viability, proliferation, and clonogenicity and altered the saturation profile of fatty acids across multiple lipid classes. The relative saturation of ceramides was the most variable between treatment conditions. MYC overexpression in the murine Meibomian gland promoted proliferation while suppressing sebaceous differentiation. Subsequent topical FASN inhibition further reduced sebaceous differentiation, attenuated PLIN2 expression, and induced apoptotic cell death. Conclusions: Collectively, these findings suggest that MYC expression in SebCA is responsive to FASN inhibition. Pharmacologic targeting of FASN reveals a metabolic vulnerability that may serve as a target for future therapeutic development.