Disruption of Amino Acid Homeostasis by Novel ASCT2 Inhibitors Involves Multiple Targets

Abstract

The glutamine transporter ASCT2 (SLC1A5) is actively investigated as an oncological target, but the field lacks efficient ASCT2 inhibitors. A new group of ASCT2 inhibitors, 2-amino-4-bis(aryloxybenzyl)aminobutanoic acids (AABA), were developed recently and shown to suppress tumor growth in preclinical in vivo models. To test its specificity, we deleted ASCT2 in two human cancer cell lines. Surprisingly, growth of parental and ASCT2-knockout cells was equally sensitive to AABA compounds. AABA compounds inhibited glutamine transport in cells lacking ASCT2, but not in parental cells. Deletion of ASCT2 and amino acid (AA) depletion induced expression of SNAT2 (SLC38A2), the activity of which was inhibited by AABA compounds. They also potently inhibited isoleucine uptake via LAT1 (SLC7A5), a transporter that is upregulated in cancer cells together with ASCT2. Inhibition of SNAT2 and LAT1 was confirmed by recombinant expression in Xenopus laevis oocytes. The reported reduction of tumor growth in pre-clinical models may be explained by a significant disruption of AA homeostasis.

Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma

“…Elevated ASCT2 expression has been reported in many types of cancer cells (53); however, it is challenging to develop a therapy targeting ASCT2 directly because such a therapy would have to target the ASCT2 on cancer cells but not normal cells, and because amino acid transporters are generally not easily druggable (54). Glutamine analogs can block ASCT2 but also block several other glutamine transporters, including SNAT1, SNAT2, and LAT1 (55,56).…”

Genetic Ablation of the Cystine Transporter xCT in PDAC Cells Inhibits mTORC1, Growth, Survival, and Tumor Formation via Nutrient and Oxidative Stresses

“…It has been reported that xCT, together with L-type amino acid transporter 1 (LAT1/SLC7A5) and alanine-serine-cysteine transporter 2 (ASCT2/SLC1A5), comprise the "minimal set" of transporters required for cancer amino acid (AA) homeostasis and this group is known to be highly upregulated in cancer (14)(15)(16). Previously, we and others have shown that disruption/inhibition of either LAT1 or ASCT2 strongly affects AA balance and thus tumor cell growth both in vitro and in vivo (17)(18)(19)(20)(21). In this study, we investigated the importance of xCT in PDAC cells along with the role of this transporter in response to chemotherapeutic agents (gemcitabine and cisplatin) via its genomic disruption in 2 different primary PDAC cell lines-MiaPaCa-2 and Capan-2 using CRISPR-Cas9.…”

Ablation of the ASCT2 (SLC1A5) gene encoding a neutral amino acid transporter reveals transporter plasticity and redundancy in cancer cells

“…Consequently, GPNA and benzylserine inhibit cell growth more strongly than selective ASCT2 silencing. A recently reported novel ASCT2 inhibitor, which reduced in vivo tumor growth (20,21), blocks SNAT2 and LAT1 more efficiently than ASCT2 (22), also excluding its use to study the role of ASCT2. Monoclonal antibodies have been used as alternative tools to reduce ASCT2 activity.…”