Targeting amino acid metabolism for cancer therapy

Highlights

• Cellular metabolism is ‘reprogrammed’ to support tumorigenesis.

• Amino acids fulfill many metabolic requirements of proliferating cells.

• Specific metabolic pathways can be inhibited for cancer therapy.

• Microenvironment and culture conditions significantly impact metabolic phenotype.

• Drugs targeting amino acid metabolism are now undergoing clinical evaluation.

To support sustained biomass accumulation, tumor cells undergo metabolic reprogramming. Nutrient transporters and metabolic enzymes are regulated by the same oncogenic signals that drive cell-cycle progression. Some of the earliest cancer therapies used antimetabolites to disrupt tumor metabolism, and there is now renewed interest in developing drugs that target metabolic dependencies. Many cancers exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. Strategies to exploit such ‘metabolic addictions’ include depleting amino acids in blood serum, blocking uptake by transporters and inhibiting biosynthetic or catabolic enzymes. Recent findings highlight the importance of using appropriate model systems and identifying target patient groups as potential therapies advance into the clinic.

Introduction

The metabolic requirements of proliferating cells, including cancer cells, differ from those of quiescent cells. Proliferating cells must acquire and process metabolites to fulfill the biosynthetic demands of replication, while maintaining energy and redox homeostasis. This presents particular challenges within the tumor microenvironment, which is often poorly vascularized and depleted of nutrients including molecular oxygen. Consequently, cancer cells utilize a broad range of strategies to obtain metabolic fuels, such that ‘use of opportunistic modes of nutrient acquisition’ was recently described as a hallmark of cancer metabolism [1].

A seminal discovery in the field of cancer metabolism was made in the 1920s by Otto Warburg, who observed that tumor tissues consume glucose much more rapidly than surrounding healthy tissue, and ferment glucose to lactate regardless of oxygen availability (aerobic glycolysis or the Warburg effect) [2]. Subsequently, Harry Eagle noted that optimal proliferation of certain cultured mammalian cell lines requires a several-fold molar excess of glutamine over any other amino acid [3]. Indeed, glucose and then glutamine are the most rapidly consumed nutrients by many cultured cancer cell lines 4, 5, although altered metabolism of fatty acids, acetate, nucleotides, folate, proteins and several amino acids besides glutamine has also been reported [1].

Cancer cell metabolism has been targeted by drugs since the advent of modern chemotherapy. In the late 1940s, the antifolate aminopterin was used to induce remission in pediatric acute lymphoblastic leukemia (ALL) patients. Aminopterin, supplanted in the 1950s by the related drug methotrexate, competitively inhibits dihydrofolate reductase and thereby blocks recycling of tetrahydrofolate, a carrier of ‘one-carbon units’ that has essential roles in amino acid and nucleic acid metabolism [6]. Today antifolates, along with antipyrimidines and antipurines, are routinely used to treat a range of cancers, illustrating the feasibility of targeting metabolism for cancer therapy.