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

Background: 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. Methods: 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. Results: 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. Conclusions: 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.