Targeting protein prenylation for cancer therapy.
Protein farnesylation and geranylgeranylation, together referred to as prenylation, are lipid post-translational modifications that are required for the transforming activity of many oncogenic proteins, including some RAS family members. This observation prompted the development of inhibitors of farnesyltransferase (FT) and geranylgeranyl-transferase 1 (GGT1) as potential anticancer drugs. In this Review, we discuss the mechanisms by which FT and GGT1 inhibitors (FTIs and GGTIs, respectively) affect signal transduction pathways, cell cycle progression, proliferation and cell survival. In contrast to their preclinical efficacy, only a small subset of patients responds to FTIs. Identifying tumours that depend on farnesylation for survival remains a challenge, and strategies to overcome this are discussed. One GGTI has recently entered the clinic, and the safety and efficacy of GGTIs await results from clinical trials.
Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida                 33612, USA.
Norbert
N
Berndt
Andrew D
AD
Hamilton
Saïd M
SM
Sebti
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D058990:Molecular Targeted Therapy; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D009479:Neuropeptides / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects*; D016032:Randomized Controlled Trials as Topic; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009479:Neuropeptides; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D020559:Monomeric GTP-Binding Proteins