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Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors

  1. Author:
    Keshet, Rom
    Lee, Joo Sang
    Adler, Lital
    Iraqi, Muhammed
    Ariav, Yarden
    Lim, Lisha Qiu Jin
    Lerner, Shaul
    Rabinovich, Shiran
    Oren, Roni
    Katzir, Rotem
    Tishler, Hila Weiss
    Stettner, Noa
    Goldman, Omer
    Landesman, Hadas
    Galai, Sivan
    Kuperman, Yael
    Kuznetsov, Yuri
    Brandis, Alexander
    Mehlman, Tevi
    Malitsky, Sergey
    Itkin, Maxim
    Koehler, S. Eleonore
    Zhao,Yongmei
    Talsania,Keyur
    Shen,Tsai-Wei
    Peled, Nir
    Ulitsky, Igor
    Porgador, Angel
    Ruppin, Eytan
    Erez, Ayelet

  2. Author Address

    Weizmann Inst Sci, Dept Regulat Biol, Rehovot, Israel.Sheba Med Ctr, Bert W Strassburger Lipid Ctr, Tel Hashomer, Israel.NCI, Canc Data Sci Lab, Bethesda, MD 20892 USA.Sungkyunkwan Univ, Samsung Med Ctr, Samsung Adv Inst Hlth Sci & Technol, Dept Hlth Sci & Technol, Seoul, South Korea.Sungkyunkwan Univ, Sch Med, Dept Precis Med, Suwon, South Korea.Ben Gurion Univ Negev, Shraga Segal Dept Microbiol Immunol & Genet, Fac Hlth Sci, Beer Sheva, Israel.Weizmann Inst Sci, Dept Vet Resources, Rehovot, Israel.Weizmann Inst Sci, Dept Life Sci Core Facil, Rehovot, Israel.Maastricht Univ, Dept Anat & Embryol, Maastricht, Netherlands.Frederick Natl Lab Canc Res, Frederick, MD USA.Soroka Med Ctr, Legacy Heritage Oncol Ctr, Beer Sheva, Israel.Soroka Med Ctr, Dr Larry Norton Inst, Beer Sheva, Israel.Ben Gurion Univ Negev, Beer Sheva, Israel.
    1. Year: 2020
    2. Date: Sep
  2. Journal: Nature Cancer
  3. SpringerNature
    1. 1
    2. 9
    3. Pages: 894-+
  5. Type of Article: Article
  6. ISSN: 2662-1347
  1. Abstract:

    Argininosuccinate synthase (ASS1) downregulation in different tumors has been shown to support cell proliferation and yet, in several common cancer subsets ASS1 expression associates with poor patient prognosis. Here we demonstrate that ASS1 expression under glucose deprivation is induced by c-MYC, providing survival benefit by increasing nitric oxide synthesis and activating the gluconeogenic enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase by S-nitrosylation. The resulting increased flux through gluconeogenesis enhances serine, glycine and subsequently purine synthesis. Notably, high ASS1-expressing breast cancer mice do not respond to immune checkpoint inhibitors and patients with breast cancer with high ASS1 have more metastases. We further find that inhibiting purine synthesis increases pyrimidine to purine ratio, elevates expression of the immunoproteasome and significantly enhances the response of autologous primary CD8(+) T cells to anti-PD-1. These results suggest that treating patients with high-ASS1 cancers with purine synthesis inhibition is beneficial and may also sensitize them to immune checkpoint inhibition therapy. Erez and colleagues demonstrate that increased expression of arginosuccinate synthase under glucose deprivation leads to gluconeogenesis and increased purine synthesis, which when targeted can enhance response to immune checkpoint blockade.

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External Sources

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  2. DOI: 10.1038/s43018-020-0106-7
  3. View record in Web of Science®
  4. WOS: 000614878600008

Library Notes

  1. Fiscal Year: FY2020-2021
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