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Geranylgeranyltransferase I as a target for anti-cancer drugs

Mark R Philips1, Adrienne D Cox

  • 1Department of Medicine, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, New York, NY 10016, USA. philim01@med.nyu.edu

The Journal of Clinical Investigation
|May 4, 2007
PubMed

Insights

Geranylgeranyltransferase type I (GGTase-I) inhibition delays lung tumor development driven by oncogenic K-Ras. Genetic ablation of GGTase-I in mice validated its potential as an anti-cancer drug target.

Area of Science:

  • Biochemistry
  • Oncology
  • Genetics

Background:

  • Posttranslational modification is crucial for Ras oncogene function, frequently altered in cancer.
  • Ras proteins are modified by farnesyltransferase (FTase), while related GTPases use geranylgeranyltransferase type I (GGTase-I).
  • Inhibitors targeting FTase are in clinical trials, prompting investigation into GGTase-I as a therapeutic target.

Purpose of the Study:

  • To investigate the role of GGTase-I in K-Ras-driven lung tumorigenesis.
  • To validate GGTase-I as a potential therapeutic target for lung cancer.

Main Methods:

  • Development of a mouse model with a conditional GGTase-I knockout allele.
  • Genetic ablation of the GGTase-I gene in lung tumor cells driven by oncogenic K-Ras.

Main Results:

  • Ablation of GGTase-I significantly delayed the onset of lung tumors.
  • Decreased tumor severity was observed in mice lacking GGTase-I.
  • These findings support the role of GGTase-I in promoting K-Ras-driven lung cancer.

Conclusions:

  • GGTase-I plays a critical role in the development and progression of K-Ras-driven lung cancer.
  • Targeting GGTase-I represents a promising strategy for anti-cancer drug development.
  • Genetic validation in a mouse model supports GGTase-I as a viable therapeutic target.

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