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Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets
Edward W Tate1,2, Lior Soday3, Ana Losada de la Lastra3
1Department of Chemistry, Imperial College London, London, UK. e.tate@imperial.ac.uk.
Abstract:
Protein lipidation describes a diverse class of post-translational modifications (PTMs) that is regulated by over 40 enzymes, targeting more than 1,000 substrates at over 3,000 sites. Lipidated proteins include more than 150 oncoproteins, including mediators of cancer initiation, progression and immunity, receptor kinases, transcription factors, G protein-coupled receptors and extracellular signalling proteins. Lipidation regulates the physical interactions of its protein substrates with cell membranes, regulating protein signalling and trafficking, and has a key role in metabolism and immunity. Targeting protein lipidation, therefore, offers a unique approach to modulate otherwise undruggable oncoproteins; however, the full spectrum of opportunities to target the dysregulation of these PTMs in cancer remains to be explored. This is attributable in part to the technological challenges of identifying the targets and the roles of protein lipidation. The early stage of drug discovery for many enzymes in the pathway contrasts with efforts for drugging similarly common PTMs such as phosphorylation and acetylation, which are routinely studied and targeted in relevant cancer contexts. Here, we review recent advances in identifying targetable protein lipidation pathways in cancer, the current state-of-the-art in drug discovery, and the status of ongoing clinical trials, which have the potential to deliver novel oncology therapeutics targeting protein lipidation.
Insights
Protein lipidation, a key post-translational modification (PTM) affecting over 1,000 proteins, offers novel cancer therapy targets. Research is advancing to identify and drug these pathways for new oncology treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Protein lipidation is a crucial post-translational modification (PTM) involving over 40 enzymes and 1,000 substrates.
- Dysregulated lipidation impacts cancer initiation, progression, and immunity, affecting key proteins like oncoproteins and signaling molecules.
- Targeting lipidation pathways presents a unique strategy for modulating 'undruggable' oncoproteins in cancer therapy.
Purpose of the Study:
- To review recent advancements in identifying targetable protein lipidation pathways in cancer.
- To summarize the current state-of-the-art in drug discovery for lipidation-modulating therapies.
- To outline the status of clinical trials for novel oncology therapeutics targeting protein lipidation.
Main Methods:
- Literature review of recent scientific publications and clinical trial data.
- Analysis of technological challenges in identifying lipidation targets and their roles.
- Comparison of lipidation PTMs with more established PTMs like phosphorylation and acetylation in cancer drug discovery.
Main Results:
- Over 150 oncoproteins are lipidated, influencing cancer cell signaling, trafficking, metabolism, and immunity.
- Technological hurdles in target identification and understanding lipidation's role in cancer persist.
- Drug discovery for lipidation pathways lags behind other PTMs, with limited clinical trials currently underway.
Conclusions:
- Protein lipidation pathways represent a promising, yet underexplored, frontier for cancer therapeutics.
- Overcoming technological challenges is critical for unlocking the full therapeutic potential of targeting protein lipidation in oncology.
- Advancements in identifying targets and ongoing clinical trials offer hope for novel cancer treatments modulating protein lipidation.
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