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

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.

The Ubiquitin–Proteasome System in Tumor Metabolism

“…FA synthesis is regulated by SREBP, a transcription factor for lipid synthase [ 61 ] that exists as an inactive precursor located on the endoplasmic reticulum (ER). When the level of lipids in tumor cells is relatively low, SREBP is cleaved at the N-terminal and the cleavage fragment is transported to the nucleus, where it binds to SRE protein and induces the expression of target genes [ 62 ].…”

The lipid droplet in cancer: From being a tumor‐supporting hallmark to clinical therapy

“…FASN, a key enzyme in the initial stage of lipid synthesis, combines acetyl‐CoA with malonyl‐CoA and converts them into long‐chain FAs 92 . FASN has been demonstrated to be overexpressed in numerous solid and hematopoietic tumors, including non‐small‐cell lung cancer (NSCLC), 93 breast cancer, 94 pancreatic cancer, 95 and lymphoma 96 . TVB‐2640, the first FASN inhibitor to enter clinical research, displayed a gratifying tolerability profile with no significant gastrointestinal or serum chemical toxicity in a phase I clinical trial (NCT02223247).…”

“…92 FASN has been demonstrated to be overexpressed in numerous solid and hematopoietic tumors, including non-small-cell lung cancer (NSCLC), 93 breast cancer, 94 pancreatic cancer, 95 and lymphoma. 96 TVB-2640, the first FASN inhibitor to enter clinical research, displayed a gratifying tolerability profile with no significant gastrointestinal or serum chemical toxicity in a phase I clinical trial (NCT02223247). Its phase II clinical trial, involving KRAS MUT NSCLC (NCT03808558), breast cancer (NCT03179904), and prostate cancer, recently commenced recruitment.…”

Orchestral role of lipid metabolic reprogramming in T-cell malignancy

“…Moreover, the SREBP1 level in transplantable T-cell lymphoma was suggested to provide an advantage in cell survival ( 106 ). The inhibition of SREBP in cutaneous T-cell lymphoma (CTCL) reduced the FASN expression partially ( 31 ). It suggests that FASN has an additional regulatory arrangement, at least in T-cell malignancies.…”

“…Lipogenic, as well as oxidative metabolism of lipids, has been targeted in T-cell cancer ( 22 , 30 ). As the metabolic pathways are intervened and compensate for each other, combinatorial and dual targeting has provided enhanced success ( 31 ). Understanding various dimensions of lipid metabolism in the life of T cells, their subsets, and their rewiring in malignant T cells is expected to open avenues for therapeutic targeting of molecular players within.…”