N-myristoylation is the irreversible attachment of myristate (a C14 fatty acid) to the N-terminal glycine of a given substrate. The enzyme responsible for this reaction is N-myristoyl transferase (NMT), a protein shown to be essential for many organisms, ranging from eukaryotes, plants, fungi, to infectious parasites. Initially, the NMTs of the fungi and infectious parasites sparked the interest of researchers in drug discovery to target these pathogens. However, the question remained whether one could target NMT in cancer. While early studies suggested potential upregulation of NMT1 in some early stage cancers, it remained unclear which cancer types to target and for which mechanistical reason.
In this study, data from pharmacogenomics screens across hundreds of cancer cell lines, treated with three different NMT inhibitors, were analysed. Haematological malignancies were amongst the most responsive cell lines; however, also cancers originating from other tissues were sensitive, indicating a more complicated picture. Detailed phenotypical and omics-based analysis of the effects of NMT inhibition in an example cancer cell line from the haematological malignancies, and an unbiased bioinformatics approach across the pharmacogenomics data hinted at the same protooncogene: MYC. Two different isogenic system with inducible MYC confirmed that MYC deregulated cells are highly dependent on myristoylation.
This newly uncovered synthetic lethality has potentially wide implications as MYC, a key transcription factor, is commonly deregulated in cancer and involved in most of the hallmarks of cancer. Targeting MYC or its downstream program attracted wide attention of the field; however, to date no drug has been approved to specifically target either. Novel approaches to target MYC, in the context of cancer, are urgently needed, and this study identified a potential new one.