Concomitant Inhibition of FASN and SREBP Provides a Promising Therapy for CTCL

SIMPLE SUMMARY: The biosynthesis of fatty acids catalysed by FASN plays an important oncogenic role in various malignancies but has not been reported in CTCL yet. Here, we show that FASN is highly expressed in both cell lines and primary cells from CTCL patients. The inhibition of FASN impairs cell viability, survival, and proliferation. FASN expression is partly controlled by SREBP, and dual inhibition of FASN and SREBP enhances the impairment of cell proliferation. Overall, our data suggest that the combination of FASN and SREBP inhibitors could be a promising novel strategy in CTCL therapy. ABSTRACT: Cutaneous T cell lymphoma (CTCL) is a group of non-Hodgkin’s primary cutaneous T cell lymphomas, with Mycosis Fungoides and Sézary syndrome (SS) being the two most common subtypes. Fatty acid synthase (FASN) is a crucial enzyme that catalyses the biosynthesis of fatty acids, which has been reported to play an oncogenic role in various malignancies but not in CTCL so far. Herein, we show that FASN is highly expressed in CTCL cell lines and in peripheral blood mononuclear cells (PBMCs) from CTCL patients, while it is not in PBMCs from healthy individuals. The inhibition of FASN in CTCL cell lines impairs cell viability, survival, and proliferation, but, interestingly, it also increases FASN expression. However, inhibiting sterol regulatory element binding protein (SREBP), a transcription factor that promotes the expression of FASN, partially reversed the upregulation of FASN induced by FASN inhibitors. Thus, the combination of FASN and SREBP inhibitors enhanced the effects on both CTCL cell lines and PBMCs from SS patients, where a valid inhibition on cell proliferation could be verified. Importantly, compared to non-malignant cells, primary malignant cells are more sensitive to the inhibition of FASN and SREBP, making the combination of FASN and SREBP inhibitors a promising novel therapeutic strategy in CTCL.