Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy

Lessons from mechanism and bench-to-bedside translational studies

Saïd M. Sebti, Andrew Hamilton

Research output: Contribution to journalArticle

Abstract

In 1990, more than 10 years after the discovery that the low molecular weight GTPase Ras is a major contributor to human cancer, farnesylation, a lipid posttranslational modification required for the cancer-causing activity of Ras, emerged as a major target for the development of novel anticancer agents. However, it took only 5 years from 1993, when the first farnesyltransferase inhibitors (FTIs) were reported, to 1998 when results from the first phase I clinical trials were described. This rapid progress was due to the demonstration of outstanding antitumor activity and lack of toxicity of FTIs in preclinical models. Although, many FTIs are currently in phase II and at least one is in phase III clinical trial, the mechanism of FTI antitumor activity is not known. In this review a brief summary of the development of FTIs as antitumor agents will be given. The focus of the review will be on important mechanistic and bench-to-bedside translational issues. Among the issues that will be addressed are: evidence for and against inhibition of the prenylation of Ras and RhoB proteins in the mechanism of action of FTIs; implications of the alternative prenylation of K-Ras by geranylgeranyl-transferase I (when FTase is inhibited) in cancer therapy; GGTase I inhibitors (GGTIs) as antitumor agents; effects of FTIs and GGTIs on cell cycle machinery and progression and potential mechanisms by which FTIs and GGTIs induce apoptosis in human cancer cells. A thorough discussion about bench-to-bedside issues relating to hypothesis-driven clinical trials with proof-of-principle in man will also be included. This section will cover issues relating to whether the biochemical target (FTase) is inhibited and the level of inhibition of FTase required for clinical response; are signaling pathways such as H-Ras/PI3K/ Akt and/or K-Ras/Raf/MEK/Erk relevant biological readouts?; is Ras (particularly N-Ras and H-Ras) mutation status a good predictor of clinical response?; in phase I trials should effective biological dose, not maximally tolerated dose, be used to determine phase II dose?; and finally, in phase II/III trials what are the most appropriate clinical end points for anti-signaling molecules such as FTIs? Parts of this topic have been recently reviewed (Sebti and Hamilton, 2000c).

Original languageEnglish (US)
Pages (from-to)6584-6593
Number of pages10
JournalOncogene
Volume19
Issue number56
DOIs
StatePublished - Dec 27 2000

Fingerprint

Farnesyltranstransferase
Prenylation
Neoplasms
Antineoplastic Agents
ras Proteins
Therapeutics
rhoB GTP-Binding Protein
geranylgeranyltransferase type-I
Phase III Clinical Trials
Clinical Trials, Phase I
Maximum Tolerated Dose
Mitogen-Activated Protein Kinase Kinases
Post Translational Protein Processing
Transferases
Phosphatidylinositol 3-Kinases
Cell Cycle
Molecular Weight
Clinical Trials
Apoptosis
Lipids

Keywords

  • Cancer therapy
  • Farnesyltransferase
  • FTI
  • Geranylgeranyltransferase I
  • GGTI
  • Hypothesis-driven clinical trials
  • Ras

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

Farnesyltransferase and geranylgeranyltransferase I inhibitors and cancer therapy : Lessons from mechanism and bench-to-bedside translational studies. / Sebti, Saïd M.; Hamilton, Andrew.

In: Oncogene, Vol. 19, No. 56, 27.12.2000, p. 6584-6593.

Research output: Contribution to journalArticle

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