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Updated: Jun 3, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
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mTOR Variants Activation Discovers PI3K-like Cryptic Pocket, Expanding Allosteric, Mutant-Selective Inhibitor Designs

Yonglan Liu1, Wengang Zhang1, Hyunbum Jang1,2

  • 1Cancer Innovation Laboratory, National Cancer Institute, Frederick, Maryland 21702, United States.

Journal of Chemical Information and Modeling
|January 10, 2025
PubMed

Insights

Understanding how mutations activate mTOR, a key protein in PI3K/AKT/mTOR signaling, can guide cancer drug development. Targeting these activation mechanisms may lead to new therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The PI3K/AKT/mTOR signaling pathway is frequently dysregulated in cancer.
  • Mammalian target of rapamycin (mTOR) is a central kinase in this pathway, and its aberrant activation drives oncogenesis.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying mTOR activation by oncogenic mutations.
  • To explore how these mechanisms can inform the design of novel therapeutic strategies targeting mTOR.

Main Methods:

  • Combined cancer genomic data analysis with extensive molecular dynamics simulations.
  • Focused on oncogenic variants of the mTOR kinase domain.

Main Results:

  • Mutations disrupt the alpha-helix packing in the mTOR kinase domain, creating a cryptic pocket.
  • This pocket's opening correlates with catalytic cleft opening and active site residue realignment, promoting catalysis.
  • The identified cryptic pocket resembles the allosteric pocket of PI3Kα and can be targeted by PI3Kα allosteric inhibitors like RLY-2608.

Conclusions:

  • Knowledge of mTOR activation mechanisms can guide the development of innovative allosteric inhibitors.
  • Drugs designed to restore the packed alpha-structure could inactivate oncogenic mTOR conformations.

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