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Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells
10:27

Spatio-Temporal Manipulation of Small GTPase Activity at Subcellular Level and on Timescale of Seconds in Living Cells

Published on: March 9, 2012

Tumorigenic activity and therapeutic inhibition of Rheb GTPase

Konstantinos J Mavrakis1, Hong Zhu, Ricardo L A Silva

  • 1Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Genes & Development
|August 19, 2008
PubMed

Insights

Rheb GTPase rapidly drives aggressive lymphomas by activating mTORC1, impacting apoptosis and drug resistance. Farnesyltransferase inhibitors block Rheb, offering a potential cancer therapy targeting Rheb and eIF4E.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • The AKT-mTOR pathway is crucial in cell signaling, regulating growth, proliferation, and survival, and is frequently dysregulated in cancer.
  • Aberrant activation of mTORC1 signaling is implicated in various cancers, including lymphoma, making it a key therapeutic target.
  • Understanding upstream regulators and downstream effectors of mTORC1 is vital for developing effective cancer treatments.

Purpose of the Study:

  • To identify genes involved in lymphomagenesis by screening candidates upstream and downstream of mTOR.
  • To investigate the role of Rheb GTPase as a proximal activator of mTORC1 in lymphoma development.
  • To evaluate the therapeutic potential of targeting Rheb and its downstream effectors, such as eIF4E, in cancer.

Main Methods:

  • Phenotypic screening in vivo to identify genes promoting lymphomagenesis.
  • In vivo testing of Rheb's role in lymphoma development and its dependence on farnesylation.
  • Pharmacological inhibition using farnesyltransferase inhibitors (FTIs) and assessment of drug resistance mechanisms.
  • Analysis of downstream targets, including translation initiation factor eIF4E, in lymphomagenesis.

Main Results:

  • Rheb GTPase was identified as a potent activator of mTORC1, rapidly inducing aggressive and drug-resistant lymphomas.
  • Rheb-induced effects on apoptosis, senescence, and treatment response mimicked Akt signaling.
  • Rheb's activity requires farnesylation and is inhibited by FTIs, demonstrating FTI efficacy in Pten-deficient tumors.
  • High RHEB expression in human lymphomas correlates with mTORC1 activation and sensitivity to rapamycin and FTIs.
  • Only eIF4E, among tested translation factors, enhanced lymphomagenesis in vivo.

Conclusions:

  • Rheb GTPase acts as an oncogenic driver upstream of mTORC1 and eIF4E, promoting aggressive lymphoma.
  • Rheb is a direct therapeutic target for farnesyltransferase inhibitors in cancer treatment.
  • FTI therapy efficacy is linked to Rheb farnesylation and can be overcome by farnesylation-independent Rheb mutants.

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