2. Academic Validation
  3. Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase

Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase

  • Cell Rep. 2017 Jun 27;19(13):2665-2680. doi: 10.1016/j.celrep.2017.05.043.
Natasha Emmanuel 1,  Shoba Ragunathan 1,  Qin Shan 1,  Fang Wang 1,  Andreas Giannakou 1,  Nanni Huser 2,  Guixian Jin 1,  Jeremy Myers 1,  Robert T Abraham 3,  Keziban Unsal-Kacmaz 4
Affiliations

Affiliations

  • 1 Oncology R&D Group, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, NY 10965, USA.
  • 2 Oncology R&D Group, Pfizer Worldwide Research and Development, 10646 Science Center Drive/CB4, San Diego, CA 92121, USA.
  • 3 Oncology R&D Group, Pfizer Worldwide Research and Development, 10646 Science Center Drive/CB4, San Diego, CA 92121, USA. Electronic address: robert.abraham@pfizer.com.
  • 4 Oncology R&D Group, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, NY 10965, USA. Electronic address: keziban.unsal-kacmaz@pfizer.com.
PMID: 28658616 DOI: 10.1016/j.celrep.2017.05.043
Abstract

Pharmacologic agents that interfere with nucleotide metabolism constitute an important class of Anticancer agents. Recent studies have demonstrated that mTOR complex 1 (mTORC1) inhibitors suppress de novo biosynthesis of pyrimidine and purine nucleotides. Here, we demonstrate that mTORC1 itself is suppressed by drugs that reduce intracellular purine nucleotide pools. Cellular treatment with AG2037, an inhibitor of the purine biosynthetic Enzyme GARFT, profoundly inhibits mTORC1 activity via a reduction in the level of GTP-bound Rheb, an obligate upstream activator of mTORC1, because of a reduction in intracellular guanine nucleotides. AG2037 treatment provokes both mTORC1 inhibition and robust tumor growth suppression in mice bearing non-small-cell lung Cancer (NSCLC) xenografts. These results indicate that alterations in purine nucleotide availability affect mTORC1 activity and suggest that inhibition of mTORC1 contributes to the therapeutic effects of purine biosynthesis inhibitors.

Keywords

AG2037; ATP; GARFT; GART; GTP; Rheb; farnesylation; mTORC1; pemetrexed; purine biosynthesis.

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