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Targeting protein prenylation for cancer therapy
Open accessAbstract
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.
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“This modification was the target of an active pipeline of farnesyltransferase inhibitors and yielded preclinical responses however limited responses in clinical trials12.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [12]
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“333 One of the reasons for the discrepancy between laboratory fi ndings and clinical trial results is that in tumours with predominantly K-Ras and N-Ras mutations, K-Ras and N-Ras can escape FTI-mediated inhibition through alternative geranylgeranylation and thus continue to retain signalling…”
BackgroundRegulation of TOR by small GTPases
Durán, R. V., & Hall, M. N. (2012) · The EMBO Reports · doi:10.1038/embor.2011.257 · Cited by 102
“mTOR and small GTPases are therapeutic targets in the treatment of cancer (Berndt et al , 2011; Dazert & Hall, 2011).”
Targeting KRAS in pancreatic cancer: new drugs on the horizon
Bannoura, S. F., Uddin, M. H., Nagasaka, M., Fazili, F., Hallak, M. N. A., Philip, P. A., El‐Rayes, B. F., & Azmi, A. S. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-09990-2 · Cited by 112
Small G Proteins in the Cardiovascular System: Physiological and Pathological Aspects
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KRAS Protein Stability Is Regulated through SMURF2: UBCH5 Complex-Mediated β-TrCP1 Degradation
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BackgroundProtein Termini and Their Modifications Revealed by Positional Proteomics
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Peptide Lipidation – A Synthetic Strategy to Afford Peptide Based Therapeutics
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“A Synthetic Strategy to Afford Peptide Based Therapeutics 190 therapies (Wang and Casey 2016; Berndt et al. 2011).”
BackgroundMethodSIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a
Jing, H., Zhang, X., Wisner, S., Chen, X., Spiegelman, N. A., Linder, M. E., & Lin, H. (2017) · eLife · doi:10.7554/elife.32436 · Cited by 102
“Co-immunoprecipitation demonstrated that neither the 3KR mutation nor Sirt2 KD altered the binding of K-Ras4a-G12V with Raf1, PI3K, or RalGDS (Figure 6—figure supplement 2a).”
BackgroundInfluentialFarnesyl diphosphate synthase is important for the maintenance of glioblastoma stemness
Kim, H. Y., Kim, D.-K., Bae, S.-H., Gwak, H., Jeon, J. H., Kim, J.-K., Lee, B. I., You, H. J., Shin, D. H., Kim, Y.-H., et al. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0166-2 · Cited by 98
Systemic treatment of pancreatic cancer revisited
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Global profiling of protein lipidation using chemical proteomic technologies
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“Prenylation has been widely studied as a drug target in cancer [43] and progeria [44], with prenyl transferase inhibitors (PTIs) entering more than 70 clinical trials [45]; as a result, a plethora of inhibitor classes is available for these enzymes, with the notable exception of RabGGTase for which a highly selective…”
BackgroundCancer of the Pancreas: Molecular Pathways and Current Advancement in Treatment
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“Phosphodiesterase delta (PDEδ) is a prenyl binding protein and interacts with prenylated K-Ras to aid K-Ras to translocate to the membrane (154, 155).”
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“Geranylgeranyltransferase (GGT) complexes transfer GGPP to small GTP-binding protein targets [65].”
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“Isoprenoids are lipid moieties that are essential for posttranslational modification, membrane anchoring, and transforming activity of Ras and Rho proteins (23, 35).”
BackgroundKerkour, A., Marquevielle, J., Иващенко, С. А., Yatsunyk, L. A., Mergny, J., & Salgado, G. F. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.781906 · Cited by 95
“Current existing strategies involve targeting post-translational modifications to prevent membrane association (75), small GTPase-targeting peptides (76), SOS-mediated nucleotide exchange (77), and inhibitors that allosterically control GTP affinity (38).”
BackgroundPharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis
Yin, C., Zhu, B., Zhang, T., Liu, T., Chen, S., Liu, Y., Li, X., Miao, X., Li, S., Mi, X., et al. (2019) · Cell · doi:10.1016/j.cell.2019.01.002 · Cited by 94
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KRAS G12C inhibitor combination therapies: current evidence and challenge
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“Prenylation by FTase activates RAS and RHEB proteins through proper membrane localization leading to cell proliferation through the RAS – RAF – MEK – ERK and PI3K – AKT – mTOR pathways (82, 83).”
BackgroundChemical Methods for Encoding and Decoding of Posttranslational Modifications
Chuh, K. N., Batt, A. R., & Pratt, M. R. (2016) · Cell chemical biology · doi:10.1016/j.chembiol.2015.11.006 · Cited by 90
“Substrate proteins of S-prenylation require the modification for membrane association and subsequent regulation of function (Berndt et al., 2011; F. L. Zhang and Casey, 1996).”
BackgroundCould drugs inhibiting the mevalonate pathway also target cancer stem cells?
Likus, W., Siemianowicz, K., Bieńk, K., Pakula, M. M., Pathak, H., Dutta, C., Wang, Q., Shojaei, S., Assaraf, Y. G., Ghavami, S., et al. (2016) · Drug Resistance Updates · doi:10.1016/j.drup.2016.02.001 · Cited by 88
Direct inhibition of RAS: Quest for the Holy Grail?
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Direct Targeting of Rab‐GTPase–Effector Interactions
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T lymphocyte regulation by mevalonate metabolism
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“Ras activates not only the MAPK signaling cascade but also the phosphoinositide 3-kinase (PI3K)–AKT pathway (46, 47), which is also activated during IL-2– and IL-15–induced effector T cell responses (Fig.”
BackgroundGeranylgeranylation signals to the Hippo pathway for breast cancer cell proliferation and migration
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Drugging the Small GTPase Pathways in Cancer Treatment: Promises and Challenges
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“Nevertheless, it has been claimed that the normally administered doses of salirasib are insufficient to inhibit the growth of lung carcinomas that carry mutations in Ras [98], failing in most in vivo assays due to the compensatory action of geranylgeranyl transferases [34,99].”
BackgroundPhase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)
the Cancer and Leukemia Group B, Gajewski, T. F., Salama, A. K. S., Niedzwiecki, D., Johnson, J. E., Linette, G. P., Bucher, C. J., Blaskovich, M. A., Sebti, S. M., & Haluska, F. G. (2012) · Journal of Translational Medicine · doi:10.1186/1479-5876-10-246 · Cited by 85
“Thus, FTIs may in fact target multiple signaling molecules that contribute to malignant transformation and are no longer viewed as pure RAS inhibitors [27].”
BackgroundInfluentialSelf-citation
Metadata
- Authors
- Berndt, N., Hamilton, A. D., & Sebti, S. M.
- Affiliations
- Moffitt Cancer Center (US)
- University of Oxford (GB)
- ORCID
- Hamilton, Andrew D.
- Venue
- Nature Reviews Cancer
- Published
- 2011-10-24
- Volume
- 11
- Issue
- 11
- Pages
- 775-791
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- PMC
- PMC4037130
- OpenAlex
- W2002252224
- Cited by
- 614
- References
- 221
- Citations by year
- 2026: 25 · 2025: 24 · 2024: 20 · 2023: 42 · 2022: 34 · 2021: 52 · 2020: 59 · 2019: 46 · 2018: 42 · 2017: 46 · 2016: 52 · 2015: 47 · 2014: 48 · 2013: 44 · 2012: 30
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA098473, U19CA067771, CA067771, R01CA098473)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- protein prenylation, farnesylation, geranylgeranylation, farnesyltransferase inhibitors, signal transduction, cell cycle progression, tumor cell survival, anticancer drug development, clinical trial results
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Animals, Antineoplastic Agents, Cell Cycle, Cell Survival, Enzyme Inhibitors, Humans, Neoplasms, Neuropeptides, Signal Transduction, Randomized Controlled Trials as Topic, Protein Prenylation, Alkyl and Aryl Transferases, Monomeric GTP-Binding Proteins, Cell Proliferation, Farnesyltranstransferase, Molecular Targeted Therapy
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