TVB-3664

Our study reveals a distinct lipid signature in gastric metaplasia characterized by TG and LD accumulation, providing novel therapeutic insights into targeting lipid metabolism to prevent GIM malignant transformation and reduce cancer risk.

Pharmacological inhibition of key nodes-such as FASN (Orlistat, TVB-3664), sphingomyelin synthase (D609), or cholesterol synthesis (statins, Genkwadaphnin)-synergizes with sorafenib/lenvatinib and overcomes resistance. We conclude that targeting lipid metabolic reprogramming, alone or combined with conventional therapies, offers significant potential for novel HCC treatment strategies. Future efforts should focus on overcoming metabolic plasticity and optimizing combinatorial regimens.

Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain...Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients.

Three related FASN inhibitors were used; TVB-3664, TVB-3166 and clinical stage TVB-2640 (denifanstat). These results demonstrate that FASN inhibition attenuates inflammatory and fibrotic drivers of NASH by direct inhibition of immune and stellate cells, beyond decreasing fat accumulation in hepatocytes. FASN inhibition therefore provides an opportunity to target three key hallmarks of NASH.

This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.

LAKR in KRAS cancers may represent an independent negative prognostic factor for patients with KRAS LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRAS and FASN inhibitors in patients with KRAS LAKR is warranted.

Importantly, combinatorial treatment of primary and established colorectal cancer cells with TVB-3664 and sulfosuccinimidyl oleate shows a synergistic effect on cell proliferation. In summary, our study demonstrates that upregulation of CD36 expression is a potential compensatory mechanism for fatty acid synthase inhibition and that inhibition of CD36 can improve the efficacy of fatty acid synthase-targeted therapy.