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

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

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Pages (from-to)894-908
Number of pages15
JournalNature Cancer
Volume1
Issue number9
DOIs
StatePublished - 1 Sep 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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