Targeting CES1 nei tumori umani

Acute Myeloid Leukemia (AML) is a highly lethal disease often characterized by a profound metabolic reprogramming that enables leukemic cells to survive under conditions of energy and environmental stress, contributing to chemotherapy resistance. Specifically, AML cells can flexibly rely on oxidative phosphorylation (OXPHOS) and reprogrammed lipid metabolism to meet their high energy demands and sustain survival and proliferation under stress. Moreover, constitutive activation of the NF-κB pathway is a frequent feature of AML, promoting survival, inflammation, and treatment resistance. Recently, carboxylesterase 1 (CES1) has been identified as an NF-κB-regulated lipase that regulates lipid catabolism, thereby facilitating energy production under nutrient-depleted conditions. However, how NF-κB-driven programs and CES1-dependent lipid metabolism intersect with bioenergetic adaptation in AML has not been defined. This study aimed to characterize the contribution of CES1 to metabolic adaptation under energy stress (ES) in AML and to evaluate the antileukemic effects of CES1 inhibition. We demonstrated that in basal conditions, all AML cell lines displayed a predominantly glycolytic phenotype, whereas ES induced a metabolic shift towards OXPHOS and upregulated CES1. Indeed, pharmacological inhibition of CES1 with the commercially available inhibitor GR-148672X resulted in impaired OXPHOS and induced ferroptosis or apoptosis in all AML lines analyzed. Genetic knockdown of CES1 confirmed the reduced cell survival observed with pharmacological inhibition. In vivo, GR-148672X slowed the tumor growth in the THP1 xenograft model. Furthermore, the combined treatment with GR-148672X and BCL-2 inhibitor, venetoclax, revealed heterogeneous interactions across the cell line panel, with synergistic cytotoxicity in specific AML cells. Collectively, these data reinforce the concept that targeting metabolic adaptation, specifically through CES1 inhibition, may provide a novel and effective therapeutic approach in AML.