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.
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