Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models

Michael L. Schulte, Allie Fu, Ping Zhao, Jun Li, Ling Geng, Shannon T. Smith, Jumpei Kondo, Robert J. Coffey, Marc O. Johnson, Jeffrey C. Rathmell, Joe T. Sharick, Melissa C. Skala, Jarrod A. Smith, Jordan Berlin, M. Kay Washington, Michael L. Nickels, H. Charles Manning

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

The unique metabolic demands of cancer cells underscore potentially fruitful opportunities for drug discovery in the era of precision medicine. However, therapeutic targeting of cancer metabolism has led to surprisingly few new drugs to date. The neutral amino acid glutamine serves as a key intermediate in numerous metabolic processes leveraged by cancer cells, including biosynthesis, cell signaling, and oxidative protection. Herein we report the preclinical development of V-9302, a competitive small molecule antagonist of transmembrane glutamine flux that selectively and potently targets the amino acid transporter ASCT2. Pharmacological blockade of ASCT2 with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in oncology, representing a new class of targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell metabolism.

Original languageEnglish
Pages (from-to)194-202
Number of pages9
JournalNature medicine
Volume24
Issue number2
DOIs
StatePublished - Feb 1 2018
Externally publishedYes

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    Schulte, M. L., Fu, A., Zhao, P., Li, J., Geng, L., Smith, S. T., Kondo, J., Coffey, R. J., Johnson, M. O., Rathmell, J. C., Sharick, J. T., Skala, M. C., Smith, J. A., Berlin, J., Kay Washington, M., Nickels, M. L., & Charles Manning, H. (2018). Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nature medicine, 24(2), 194-202. https://doi.org/10.1038/nm.4464