Targeting cancer metabolism: Therapeutic potential of the fatty acid synthase (FASN) inhibitors

Abstract

Metabolic rewiring is a hallmark of cancer, enabling tumor cells to proliferate rapidly and survive under adverse conditions. Fatty acid synthase (FASN), a key enzyme in de novo lipogenesis, is significantly upregulated in various cancers and is associated with poor prognosis and increased tumor aggressiveness. This review examines the crucial role of FASN in cancer metabolism and evaluates the therapeutic potential of FASN inhibitors. We explore the metabolic pathways critically regulated by FASN and outline its structure, function, and regulatory mechanisms. Overexpression of FASN occurs in cancers such as lung, colon, brain, breast, and prostate, where clinical trials have either been conducted or are ongoing. Pharmacologic inhibition of FASN disrupts lipid biosynthesis, leading to accumulation of metabolic intermediates, induction of metabolic stress, and cell cycle arrest/apoptosis in cancer cells. Denifanstat (TVB-2640), the first-in-class selective FASN inhibitor with favorable pharmacokinetic properties, has demonstrated robust antitumor activity in preclinical models and encouraging results in early-phase clinical studies. Clinical evidence suggests that FASN blockade not only impairs tumor growth but also potentiates the efficacy of existing treatments, including chemotherapy and targeted agents, thereby supporting its integration into combination regimens. Future clinical optimization will require the identification of predictive biomarkers to guide patient selection and treatment stratification.

Keywords: Cancer Metabolism; De Novo Lipogenesis (DNL); Denifanstat (TVB-2640); Fatty Acid Synthase (FASN) inhibitors; Lipid Biosynthesis; Metabolic Reprogramming.