l-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase

Amino acids are the fundamental building blocks for protein synthesis, and as such, contribute to the majority of biomass in proliferating cells. Amino acid metabolism also has extremely extensive effects, including, but not limited to, conversion to glucose, lipids, and nucleic acids, energy supply, maintenance of intracellular redox status, regulation of signaling pathways, epigenetic modifications and ammonia detoxification [1]. Metabolic reprogramming has been widely recognized as a hallmark of cancer [2]. Indeed, the uptake and metabolism of amino acids are upregulated in many cancers that display addiction to specific amino acids. Amino acids facilitate the survival and proliferation of cancer cells under genotoxic, oxidative, and nutritional stress [3]. Thus, amino acid depletion therapy is a promising approach to starve cancer cells to death, while leaving normal tissues intact [[4], [5], [6]]. Recent evidence suggests that asparagine (Asn) bioavailability plays a critical role in the progression of several types of cancer [[7], [8], [9]]. Asn is a non-essential amino acid supporting protein biosynthesis. Asn has been shown to promote cancer cell proliferation through use as an amino acid exchange factor regulating uptake of other amino acids such as arginine, histidine, and serine [9] and to support tumor cell adaptation to glutamine (Gln) depletion [10,11]. l-Asparaginase (ASNase), an enzyme that hydrolyzes Asn into aspartic acid (Asp) and ammonia is a cornerstone of acute lymphoblastic leukemia (ALL) therapy since lymphoblasts lack asparagine synthetase (ASNS) and rely on extracellular asparagine availability for survival [12]. Even though clinical application of ASNase is limited to ALL and some types of NK/T cell lymphoma, growing evidence suggests the potential of ASNase for the treatment of solid tumors [13]. However, lack of understanding of resistance mechanisms [[14], [15], [16]] as well as severe side effects [17] limit optimal clinical development of ASNase in solid tumors. Although resistance mechanisms have been associated with increased ASNS expression in ALL [18], the association between ASNS and ASNase efficacy in solid tumors remains unclear [19]. Interestingly, ASNase also has a glutaminase (GLNase) co-activity allowing it to hydrolyze Gln into glutamic acid (Glu) and ammonia [20]. Gln is the most abundant and versatile non-essential amino acid in the body [21], fueling the tricarboxylic acid (TCA) cycle and contributing to the biosynthesis of lipids, nucleotides, glutathione, and other non-essential amino acids. While the contribution of this glutaminase co-activity in ALL is controversial [22], recent findings indicate that solid tumors exhibit high rates of Gln consumption to support macromolecular biosynthesis and cell proliferation [23] and are severely affected by Gln depletion [24]. This is particularly true in pancreatic ductal adenocarcinoma (PDAC) where KRAS is mutationally activated in 95% of tumors, resulting in extensive reprogramming of cellular metabolism with a robust glycolytic activity and Gln addiction [25,26]. Pancreatic cancer has been increasing in incidence and is the fourth most frequent cause of cancer-related deaths worldwide with a 5-year survival of less than 8% [27]. PDAC represents more than 90% of all pancreatic malignancies [28]. Interestingly, several studies have evidenced the potential of ASNase for the treatment of pancreatic cancer [[29], [30], [31]]. Despite several attempts to decipher respective contributions of Asn and Gln depletion, the precise mechanism of action of ASNase in PDAC has not been elucidated [29,31]. In line with previous results [29], null/low ASNS expression was further observed in 79.4% of resected PDAC tumors from a cohort of 471 patients using immunohistochemistry [32]. However, recent phase IIb clinical trial demonstrated that eryaspase (ASNase entrapped in red blood cells) in combination with chemotherapy was associated with improvements in overall survival and progression-free survival in second-line advanced pancreatic adenocarcinoma, irrespective of ASNS expression [33]. Thus, the respective contribution of ASNase and GLNase activities as well as the role of ASNS as predictive marker to ASNase response in PDAC remains unclear. In this study, we developed ASNase-resistant human pancreatic cancer cell lines and used a combination of OMICS approaches to decipher the mechanism of action of ASNase in PDAC and identify potential markers of resistance.

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