Anticancer activity of farnesyltransferase and geranylgeranyltransferase I inhibitors: prospects for drug development

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Farnesyltransferase (FTase) inhibitors are investigated as anticancer drugs due to Ras oncoprotein's farnesylation requirement.
• Potent FTase inhibitors demonstrate significant antitumour activity in preclinical models without observable toxicity.

Purpose of the Study:

• To address critical issues in the development of FTase inhibitors as anticancer agents.
• To discuss K-Ras resistance mechanisms and alternative therapeutic strategies.

Main Methods:

• Review of current literature on FTase inhibitors and K-Ras resistance.
• Analysis of alternative prenylation pathways involving geranylgeranyltransferase I (GGTase I).

Main Results:

• K-Ras resistance to FTase inhibitors occurs via alternative prenylation by GGTase I.
• This resistance mechanism raises questions about K-Ras as the sole target for FTase inhibitors.

Conclusions:

• Further development of FTase inhibitors requires understanding and overcoming K-Ras resistance.
• Exploring targets beyond K-Ras and the role of GGTase I inhibitors is crucial for advancing anticancer therapies.