Abstract
Human N-myristoyltransferases (NMTs) catalyze N-terminal protein myristoylation, a modification regulating membrane trafficking and interactions of >100 proteins. NMT is a promising target in cancer, but a mechanistic rationale for targeted therapy remains poorly defined. Here, large-scale cancer cell line screens against a panel of NMT inhibitors (NMTi) were combined with systems-level analyses to reveal that NMTi is synthetic lethal with deregulated MYC. Synthetic lethality is mediated by post-transcriptional failure in mitochondrial respiratory complex I protein synthesis concurrent with loss of myristoylation and degradation of complex I assembly factor NDUFAF4, followed by mitochondrial dysfunction specifically in MYC-deregulated cancer cells. NMTi eliminated MYC-deregulated tumors in vivo without overt toxicity, providing a new paradigm in which targeting a constitutive co-translational protein modification is synthetically lethal in MYC-deregulated cancers.
One-sentence summary N-myristoyltransferase inhibition leads to post-transcriptional complex I failure and cell death in MYC-deregulated cancers
Competing Interest Statement
EWT, ASB, JAH and MF are founders and shareholders, and RS and RC are employees and shareholders, of Myricx Pharma Ltd, which holds licenses to patents covering composition and use of NMT inhibitors. EWT, ASB, JAH, DPC, GAL and MF are named as inventors on patents covering NMT inhibitors (WO2017001812A1, US2020/0339586) and synthetic lethality of NMTi in high-MYC cancers (WO2020128475).