OBJECTIVESWild type RAS (RAS^WT) suppresses the function of oncogenic RAS mutants (RAS^MUT) in laboratory models. Loss of RAS^WT, which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RAS^MUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RAS^MUT cancers is attractive as a potential biomarker for targeted therapy.MATERIALS AND METHODSWe evaluated for associations between LAKR and cancer mortality in patients with KRAS^MUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRAS^MUT LAKR, including combination strategies involving clinical KRAS^G12C and FASN inhibitors.RESULTS24 % of patients with KRAS^MUT LUAD showed LAKR. KRAS^MUT LAKR cases had a median survival of 16 vs. 30 months in KRAS^MUT non-LAKR (p =  0.017) and LAKR was independently associated with death in this cohort (p =  0.011). We also found that KRAS^MUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRAS^MUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRAS^G12C inhibitor MRTX849 in LUAD cells with KRAS^G12C and LAKR, including an in vivo trial using a xenograft model.CONCLUSIONSLAKR in KRAS^MUT cancers may represent an independent negative prognostic factor for patients with KRAS^MUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRAS^G12C and FASN inhibitors in patients with KRAS^G12C LAKR is warranted.

Scientific Reports

FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models

Article

Author: Buckley, Douglas ; Bhattacharya, Dipankar ; Crowley, Richard ; Duke, Greg ; O'Farrell, Marie ; Kemble, George ; Martins, Eduardo B ; Friedman, Scott L

AbstractFatty acid synthase (FASN) is an attractive therapeutic target in non-alcoholic steatohepatitis (NASH) because it drives de novo lipogenesis and mediates pro-inflammatory and fibrogenic signaling. We therefore tested pharmacological inhibition of FASN in human cell culture and in three diet induced mouse models of NASH. Three related FASN inhibitors were used; TVB-3664, TVB-3166 and clinical stage TVB-2640 (denifanstat). In human primary liver microtissues, FASN inhibiton (FASNi) decreased triglyceride (TG) content, consistent with direct anti-steatotic activity. In human hepatic stellate cells, FASNi reduced markers of fibrosis including collagen1α (COL1α1) and α-smooth muscle actin (αSMA). In CD4+ T cells exposed to NASH-related cytokines, FASNi decreased production of Th17 cells, and reduced IL-1β release in LPS-stimulated PBMCs. In mice with diet induced NASH l, FASNi prevented development of hepatic steatosis and fibrosis, and reduced circulating IL-1β. In mice with established diet-induced NASH, FASNi reduced NAFLD activity score, fibrosis score, ALT and TG levels. In the CCl4-induced FAT-NASH mouse model, FASN inhibition decreased hepatic fibrosis and fibrosis markers, and development of hepatocellular carcinoma (HCC) tumors by 85%. 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.

100 Deals associated with TVB-3664

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Indication	Highest Phase	Country/Location	Organization	Date
Metabolic dysfunction-associated steatotic liver disease	Preclinical	US	Sagimet Biosciences, Inc.	15 May 2024
Neoplasms	Preclinical	US	Sagimet Biosciences, Inc.	15 May 2024
Colorectal Cancer	Preclinical	US	University of Kentucky	10 Apr 2024

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