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Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance

Kenta Masui1, Kazuhiro Tanaka2, Shiro Ikegami3

  • 1Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA 92093; Laboratory of Neuropathology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan;

Proceedings of the National Academy of Sciences of the United States of America
|July 15, 2015
PubMed

Insights

Nutrient availability, specifically glucose or acetate, fuels glioblastoma growth by enabling epidermal growth factor receptor vIII (EGFRvIII) to activate mTORC2 signaling. This nutrient-driven signaling creates resistance to targeted cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Cancer cells dynamically adjust signaling pathways in response to nutrient fluctuations.
  • Glioblastoma (GBM) is an aggressive brain cancer with limited treatment options.
  • Understanding nutrient-mediated signaling is crucial for developing effective GBM therapies.

Purpose of the Study:

  • To investigate the mechanisms by which nutrient availability regulates glioblastoma growth.
  • To identify signaling pathways linking nutrient sensing to tumor progression in GBM.
  • To explore the role of nutrient-induced signaling in therapeutic resistance.

Main Methods:

  • Utilized glioblastoma cell lines, preclinical mouse tumor models, and clinical patient samples.
  • Performed molecular analyses to identify key signaling components and regulatory mechanisms.
  • Investigated the impact of glucose and acetate on growth factor receptor signaling and mTORC2 activation.

Main Results:

  • Discovered that glucose or acetate is essential for epidermal growth factor receptor vIII (EGFRvIII) to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote GBM growth.
  • Identified acetyl-CoA-dependent acetylation of Rictor as the mechanism linking nutrient availability to growth factor receptor signaling.
  • Demonstrated that elevated glucose sustains mTORC2 autoactivation, conferring resistance to EGFR-, PI3K-, and AKT-targeted therapies.

Conclusions:

  • Elevated nutrient levels can drive resistance to targeted cancer therapies in glioblastoma.
  • mTORC2 acts as a central integrator of growth factor signaling and nutrient availability in GBM.
  • Targeting mTORC2 or its nutrient-dependent regulation may overcome therapeutic resistance in GBM.
Keywords:
Rictor acetylationglioblastomamTORC2metabolic reprogrammingtargeted therapy resistance

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