L'inibizione della Carbossilesterasi 1 come strategia per bloccare la riprogrammazione metabolica delle cellule di carcinoma ovarico resistenti alla chemioterapia a base di platino

Treating ovarian cancer (OC) remains challenging. Hence, while women initially show responsiveness to platinum and taxane-based chemotherapy, the gold standard for OC treatment, they frequently relapse due to platinum resistance. The low availability of validated therapeutic targets further limits the therapeutic options, resulting in a high mortality rate of approximately 70%. Increasing evidence suggests that the metabolic adaptation of cancer cells facilitates their growth, invasiveness, and metastatic potential. Therefore, the reprogramming of energy metabolism is undoubtedly in the eye of the storm in the context of cancer research and treatment. Specifically, OC cells show addiction to lipid metabolism in advanced stages, supporting the hypothesis that fat availability plays a crucial role in promoting aggressiveness and chemoresistance. The NF-κB signaling pathway is majorly implicated in OC advanced disease, where it drives chemoresistance, stemness, metastasis and immune evasion. Although NF-κB signaling is upregulated in OC tumors and correlates with poorer clinical outcomes, there are no clinically useful specific NF-κB inhibitors. The conundrum in therapeutically blocking NF-κB has been achieving cancer-cell specificity, given the ubiquitous and pleiotropic functions of the NF-κB pathway. To overcome the toxicity associated with systemic NF-κB blockade, both academia and pharma are focused on targeting essential cancer-specific downstream effectors of oncogenic NF-κB signalling rather than NF-κB itself. Recently, CES1 has been depicted as a NF-κB-regulated triacylglycerol (TAG) lipase linking obesity-associated inflammation with lipid catabolism and metabolic adaptation to nutrient depletion-driven energy stress (ES) in aggressive colorectal carcinoma (CRC). Specifically, CES1 promotes cancer cell survival and metabolic adaptation in CRC cells under ES via two distinct cell-autonomous mechanisms: 1) First, it enables CRC cells to meet their energy demand by increasing the breakdown of TAGs stored in lipid droplets (LD) and providing free fatty acids for fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS); 2) Second, it prevents the toxic build-up of TAGs that results in reactive oxygen species (ROS) production and lipid peroxidation leading to cell death by apoptosis and ferroptosis. Alike CRC, OC shows addiction to both lipid metabolism and NF-κB and the tendency to preferentially metastasize toward the peritoneal cavity and the omentum, a fat-rich organ, making this tumor a promising setting in which investigate CES1 role. Hence, this project aimed at understanding whether CES1 could support the metabolic adaptation and survival of OC cells, to potentially identify a new druggable target to counteract aggressive OC disease. We demonstrated that OC cells mostly rely on glucose to meet their energetic demand in basal conditions, but they reprogramme their metabolism toward OXPHOS upon ES. Notably, the OC cells upregulated FAO and CES1 mRNA when cultured under ES and became resistant to platinum, suggesting that lipid metabolism and CES1 could be relevant to cope with nutrient fluctuations and this metabolic reprogramming could increase chemoresistance. Indeed, unlike carboplatin, pharmacological CES1 blockade by commercially available GR-148672X inhibitor impaired bioenergetic parameters, blocked autophagy flux and is effective in killing carboplatin-resistant OC cells. The clinical relevance of CES1 blockade is supported by the inverse correlation between CES1 expression and worse prognosis in OC patients and the capacity of CES1 inhibitors to kill primary OC cells, thus resembling OC cell lines behaviour. All together, these data underscore that CES1-driven reprogramming is mostly relevant during the metabolic reprogramming towards an oxidative phenotype and sustain the actionability of CES1 inhibition to impede autophagy, lipid catabolism and survival of platinum-resistant OC cells