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Purine Nucleotide Availability Regulates mTORC1 Activity through the Rheb GTPase
Natasha Emmanuel1, Shoba Ragunathan1, Qin Shan1
1Oncology R&D Group, Pfizer Worldwide Research and Development, 401 N. Middletown Road, Pearl River, NY 10965, USA.
Cell Reports
|June 29, 2017
Summary
Drugs inhibiting purine synthesis reduce mTORC1 activity by lowering guanine nucleotides. This mTORC1 inhibition contributes to the anticancer effects of purine biosynthesis inhibitors, particularly in non-small-cell lung cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Pharmacologic agents targeting nucleotide metabolism are crucial anticancer therapies.
- mTOR complex 1 (mTORC1) inhibitors are known to suppress de novo pyrimidine and purine biosynthesis.
- The interplay between nucleotide pools and mTORC1 signaling requires further elucidation.
Purpose of the Study:
- To investigate the effect of purine biosynthesis inhibition on mTORC1 activity.
- To determine the mechanism by which purine depletion impacts mTORC1 signaling.
- To assess the therapeutic potential of targeting purine biosynthesis and mTORC1 in non-small-cell lung cancer (NSCLC).
Main Methods:
- Utilized AG2037, a GARFT inhibitor, to reduce intracellular purine nucleotide pools.
- Assessed mTORC1 activity by measuring GTP-bound Rheb levels.
- Evaluated tumor growth suppression in NSCLC xenograft mouse models.
Main Results:
- Cellular treatment with AG2037 significantly inhibited mTORC1 activity.
- This inhibition was mediated by a reduction in intracellular guanine nucleotides, leading to decreased GTP-bound Rheb.
- AG2037 treatment resulted in robust non-small-cell lung cancer xenograft growth suppression in vivo.
Conclusions:
- Intracellular purine nucleotide availability directly influences mTORC1 activity.
- Inhibition of mTORC1 is a contributing mechanism for the therapeutic efficacy of purine biosynthesis inhibitors.
- Targeting purine metabolism offers a promising strategy for NSCLC treatment by modulating mTORC1 signaling.
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