期刊
PHARMACOLOGY & THERAPEUTICS
卷 230, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pharmthera.2021.107964
关键词
Amino acid transporters; LAT1 (SLC7A5); Drug delivery; PET; Amino acid signaling; LAT1 inhibitors; Cancer therapy
资金
- Japan Society for the Promotion of Science
- Project for Development of Innovative Research on Cancer Therapeutics from Japan Agency for Medical Research and Development
Cancer cells require a massive supply of nutrients, including amino acids. LAT1 is an amino acid transporter that is specifically expressed in cancer cells. High expression of LAT1 is associated with poor prognosis in patients. Inhibition of LAT1 can suppress cancer cell proliferation and tumor growth. LAT1 can also be used as a target for cancer diagnosis and specific delivery of anti-tumor drugs.
Cancer cells require a massive supply of nutrients, including sugars and amino acids-the upregulation of transporters for each nutrient contributes to meet the demand. Distinct from glucose transporters, amino acid transporters include ones whose expression is specific to cancer cells. For example, LAT1 (SLC7A5) displays protein expression mostly limited to the plasma membrane of cancer cells. The exceptions are the placental barrier and the blood-brain barrier, where immunohistochemical and mass spectrometric studies have shown LAT1 expression, although their levels are supposed to be lower than those in cancers. The expression of LAT1 has been reported in cancers from various tissue origins, where high LAT1 expression is related to the poor prognosis of patients. LAT1 is essential for cancer cell growth because the pharmacologic inhibition and knockdown/knockout of LAT1 suppress the proliferation of cancer cells and the growth of xenograft tumors. The inhibition of LAT1 suppresses protein synthesis by downregulating the mTORC1 signaling pathway and mobilizing the general amino acid control (GAAC) pathway in cancer cells. LAT1 is, thus, a candidate molecular target for the diagnosis and therapeutics of cancers. F-18-labeled 3-fluoro-L-alpha-methyl-tyrosine (FAMT) is used as a LAT1-specific PET probe for cancer detection due to the LAT1 specificity of alpha-methyl aromatic amino acids. FAMT accumulation is cancer-specific and avoids non-cancer lesions, including inflammation, confirming the cancer-specific expression of LAT1 in humans. Due to the cancer-specific nature, LAT1 can also be used for cancer-specific delivery of antitumor agents such as L-para-boronophenylalanine used for boron neutron capture therapy and alpha-emitting nuclide-labeled LAT1 substrates developed for nuclear medicine treatment. Based on the importance of LAT1 in cancer progression, high-affinity LAT1-specific inhibitors have been developed for anti-tumor drugs. JPH203 (KYT0353) is such a compound designed based on the structure-activity relationship of LAT1 ligands. It is one of the highest-affinity inhibitors with less affecting other transporters. It suppresses tumor growth in vivo without significant toxicity in preclinical studies at doses enough to suppress tumor growth. In the phase-I clinical trial, JPH203 appeared to provide promising activity. Because the mechanisms of action of LAT1 inhibitors are novel, with or without combination with other anti-tumor drugs, they could contribute to the treatment of cancers that do not respond to current therapy. The LAT1-specific PET probe could also be used as companion diagnostics of the LAT1-targeting therapies to select patients to whom therapeutic benefits could be expected. Recently, the cryo-EMstructure of LAT1 has been solved, which would facilitate the understanding of themechanisms of the dynamic interaction of ligands and the binding site, and further designing new compounds with higher activity. (C) 2021 Elsevier Inc. All rights reserved.
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