FASN for diffuse malignant peritoneal mesothelioma: a prognostic biomarker after CRS+HIPEC and a therapeutic target

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and aggressive malignancy with limited therapeutic options and poor clinical outcomes. While metabolic reprogramming, including altered lipid metabolism, is a recognized hallmark of cancer, its contribution to DMPM progression and treatment response remains poorly understood.

Gene expression profiling was performed on tumor samples from 45 DMPM patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC), comparing patients who developed recurrence within 30 months (N = 13) to those with later relapse or no recurrence (N = 32). Candidate prognostic markers were validated by immunohistochemistry in a cohort of 80 DMPM patients treated with CRS+HIPEC. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox regression analyses. To evaluate therapeutic potential, selective (cerulenin, C75) and non-selective (orlistat) fatty acid synthase (FASN) inhibitors were tested in patient-derived DMPM cell lines. Effects on cell proliferation, cell cycle progression, and apoptosis were assessed. Combination treatments with selinexor (XPO1/CRM1 inhibitor) or IAG-933 (inhibitor of FASN-derived palmitoyl-CoA activity) were also evaluated.

Fatty acid synthase (FASN) was significantly upregulated in tumors from patients with early recurrence. High FASN protein expression was associated with reduced PFS (HR = 1.93; p = 0.01) and OS (HR = 1.85; p = 0.02). Multivariate analysis confirmed FASN as an independent predictor of both PFS (HR = 2.24; p = 0.005) and OS (HR = 2.24; p = 0.014). In vitro, FASN inhibition significantly reduced DMPM cell growth, disrupted cell cycle progression, and induced apoptosis, with C75 showing the strongest effects. Combination treatment with FASN inhibitors and selinexor or IAG-933 resulted in enhanced growth inhibition and apoptosis compared with single-agent treatments.

FASN represents a novel independent prognostic biomarker in DMPM patients undergoing CRS+HIPEC and a promising therapeutic target. Given the limited treatment options for DMPM, combination strategies incorporating FASN inhibitors with selinexor or TEAD-pathway-targeting agents, supported by existing clinical trial data, may offer a rapidly translatable therapeutic approach.