Mechanistic insights into L-asparaginase resistance in cancers

As the most successful example of cancer therapy via amino acid starvation to date, the bacterially derived enzyme L-asparaginase (ASNase) has been used as a key chemotherapeutic agent in the treatment of acute lymphoblastic leukemia (ALL) for more than forty years, which greatly improves the clinical outcome of pediatric and adolescent patients. By degrading L-asparagine (Asn), a non-essential amino acid for normal cells, ASNase induces selective death of some Asn-auxotrophic tumor cells. However, like the inevitable resistance to most chemotherapeutic drugs developed in cancer cells, the resistance to ASNase still emerges, leading to disease relapse and poor prognosis. Moreover, most solid tumors are resistant to ASNase, with the explicit mechanisms not clearly understood, hindering its broad-spectrum application in cancer treatment. Given the lack of a thematic overview of molecular mechanisms of ASNase resistance revealed in recent decade or more, an attempt has been made in this review to outline the current application of ASNase and its resistance as a clinical problem in cancer treatment, and more efforts have been dedicated to emphasizing the summary and discussion of the updated mechanisms of ASNase resistance across different types of human cancers, proposing a complex regulatory network that underpins ASNase resistance.