TVB-3664

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.