Farnesylated proteins as anticancer drug targets: From laboratory to the clinic

Patrizia Russo, Maura Loprevite, Alfredo Cesario, Andrea Ardizzoni

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The knowledge that Ras was readily prenylated by protein FTase and that the inhibition of this reaction has the ability to revert the transformed phenotype, provided the rationale for the development of FTIs as anticancer drugs. Studies have shown that farnesylation of Ras is the first, obligatory first step in a series of post-translational modifications leading to membrane association, which, in turn, determines the switch from an inactive to an active Ras-GTP bound form. Based on the theorical assumption that preventing Ras farnesylation might result in the inhibition of Ras functions, a range of FTIs have been synthesized. Their biology is fascinating since after substantial investigation and their use in several phase II studies and at least two phase III trials, the exact mechanism of action remains unclear. FTIs can block the farnesylation of several additional proteins, such as RhoB, prelamins A and B, centromere proteins (CENP-E, CENP-F), etc. While the FTIs clearly do not or only partly target Ras, these agents appear to have clinical activity in leukemia and in some solid tumors regardless of their Ras mutational status. Although inhibition of FTase by these compounds has been well documented also in normal tissues, their toxic effects seem to be manageable. However, preliminary results of early Phase II-III studies suggest that the activity of FTIs, as a single-agent, is modest and generally lower than that obtained by standard cytotoxic drugs. Ongoing clinical studies are assessing the role of FTIs for early stage disease or in combination with cytotoxic agents or with other molecular targeted therapies for advanced stage tumors. Further insights in the molecular mechanism of action of FTIs might help in better define their optimal use in combination with standard therapies in the treatment of cancer patients.

Original languageEnglish
Pages (from-to)123-138
Number of pages16
JournalCurrent Medicinal Chemistry - Anti-Cancer Agents
Issue number2
Publication statusPublished - 2004


  • Cell cycle
  • Cytotoxicity
  • Farnesylated proteins
  • Farnesyltransferase
  • Farnesyltransferase inhibitors
  • Phase I, II, III studies
  • Ras

ASJC Scopus subject areas

  • Molecular Medicine
  • Cancer Research
  • Pharmacology


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