mTORC1 Couples Nucleotide Synthesis to Nucleotide Demand Resulting in a Targetable Metabolic Vulnerability

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Mechanistic target of rapamycin complex 1 (mTORC1) promotes cell proliferation via anabolic processes.
• mTORC1 activation is common in human cancers.
• Loss of tuberous sclerosis complex (TSC) tumor suppressors leads to mTORC1 activation and TSC disease.

Purpose of the Study:

• To investigate the metabolic coupling of anabolic processes driven by mTORC1.
• To identify therapeutic vulnerabilities in TSC-deficient cancers.

Main Methods:

• Utilized pharmacological inhibitors of guanylate nucleotide synthesis.
• Assessed effects on TSC-deficient cells and mouse tumor models.
• Investigated replication stress and DNA damage induction.

Main Results:

• Inhibitors of guanylate nucleotide synthesis selectively harmed TSC-deficient cells.
• mTORC1-driven rRNA synthesis caused replication stress and DNA damage.
• Nucleotide pool limitation was identified as a key factor.

Conclusions:

• Anabolic imbalance downstream of mTORC1 creates a metabolic vulnerability.
• Targeting guanylate nucleotide synthesis is a potential therapeutic strategy for TSC-associated cancers.