Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth

Authors

Anna Han
Dzmitry Mukha
Vivian Chua
Timothy J Purwin
Manoela Tiago
Bhavik Modasia
Usman Baqai
Jenna L Aumiller
Nelisa Bechtel
Emily Hunter
Meggie Danielson
Mizue Terai
Philip B Wedegaertner
Takami Sato
Solange Landreville
Michael A Davies
Stefan Kurtenbach
J William Harbour
Zachary T Schug
Andrew E Aplin

Publication Date

6-30-2023

Journal

Cancers

Abstract

Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.

Keywords

fatty acid synthase, mTOR pathway, metabolic inhibition, uveal melanoma, GNAQ

DOI

10.3390/cancers15133451

PMID

37444561

PMCID

PMC10341317

PubMedCentral® Posted Date

6-30-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes