De Novo Palmitate Synthesis Supports Oncogenic Signalling and Tumor Growth Through Diverse Mechanisms: Implications for FASN-Targeted Therapeutics

Timothy S Heuer

doi:10.4172/2576-1471.1000124

Abstract

Palmitate, the enzymatic product of fatty acid synthase (FASN), provides a substrate for the synthesis of longand short-chain fatty acids. Many recent studies have expanded our knowledge about the roles palmitate and lipid synthesis play in tumor cell biology beyond supporting energy metabolism and membrane building. The recent article described cell biology and pharmacology studies using a novel, selective small molecule FASN inhibitor, TVB-3166. They demonstrated that FASN inhibition disrupts oncogenic signalling and tumor growth in xenograft models through inhibition of pathways that include Wnt/beta-catenin and expression of c-Myc: potent oncogenes historically recalcitrant to direct pharmacological inhibition. Discussed here are how these findings advance our mechanistic understanding of the diverse biological roles of palmitate and its integration into various signalling pathways driving tumor cell proliferation and survival. These insights highlight the promising potential of selective, potent FASN inhibitors as a novel therapeutic strategy for cancer and other illnesses.

Highlights

Constitutive or inappropriate activation of biological signalling pathways regulating cell growth, proliferation, and survival is a wellrecognized hallmark of cancer initiation and progression [1,2,3,4,5]
The role that certain lipid species and, especially, lipids derived from de novo palmitate synthesis play in both activation and repression of oncogenic signalling recently has come into sharper focus following many advances in tools for lipid analyses and tumor biology [1,7,8,9,10,11,12,13,14,15,16,17]
Ventura et al described mechanism-based effects on tumor cell biology and in vivo xenograft tumor growth that occurred in response to inhibition of fatty acid synthase (FASN) in tumor cells from a variety of tissues and genetic backgrounds

Summary

Introduction

Constitutive or inappropriate activation of biological signalling pathways regulating cell growth, proliferation, and survival is a wellrecognized hallmark of cancer initiation and progression [1,2,3,4,5]. Profound reprogramming of gene expression and inhibition of signal transduction occurred following treatment of tumor cells with TVB-3166, a selective, reversible, and orally bioavailable small molecule FASN inhibitor (cellular palmitate synthesis IC50=42 nM) (Figure 1).

Results

Conclusion