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PMID: 22020205 Published · epublish English Journal Article Research Support, N.I.H., Extramural

Targeting protein prenylation for cancer therapy.

Nature reviews. Cancer ·Vol. 11 ·No. 11 ·2011-00-24 ·Pages 775-91

Berndt N, Hamilton AD, Sebti SM

Abstract

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.

MeSH Terms
Alkyl and Aryl Transferases/antagonists & inhibitors Animals Antineoplastic Agents/therapeutic use Cell Cycle/drug effects Cell Proliferation/drug effects Cell Survival/drug effects Enzyme Inhibitors/pharmacology,therapeutic use Farnesyltranstransferase/antagonists & inhibitors Humans Molecular Targeted Therapy Monomeric GTP-Binding Proteins/metabolism Neoplasms/drug therapy Neuropeptides/metabolism Protein Prenylation/drug effects Randomized Controlled Trials as Topic Ras Homolog Enriched in Brain Protein Signal Transduction/drug effects
Chemicals
Antineoplastic Agents Enzyme Inhibitors Neuropeptides RHEB protein, human Ras Homolog Enriched in Brain Protein Alkyl and Aryl Transferases geranylgeranyltransferase type-I Farnesyltranstransferase Monomeric GTP-Binding Proteins
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Berndt Norbert
Drug Discovery Department, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
Hamilton Andrew D
Sebti Saïd M
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Article Info
Journal
Nature reviews. Cancer
Abbr.
Nat Rev Cancer
ISSN
1474-1768
DOI
10.1038/nrc3151
Published
2011-00-24
Epub
2011-00-24
Pages
775-91
Language
English
Region
England
NLM ID
101124168
PMCID
PMC4037130
Subset
IM
Grants
NCI NIH HHS · R01 CA098473 · United States
NCI NIH HHS · U19 CA067771 · United States
NCI NIH HHS · CA067771 · United States
NCI NIH HHS · CA098473 · United States
External Links
PubMed source DOI: 10.1038/nrc3151 PMC Full Text View journal details
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