N-myristoyltransferase inhibition is synthetic lethal in MYC-deregulated cancers

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Item Type:	Preprint
Title:	N-myristoyltransferase inhibition is synthetic lethal in MYC-deregulated cancers
Creators Name:	Lueg, G.A., Faronato, M., Gorelik, A., Grocin, A.G., Caamano-Gutierrez, E., Falciani, F., Solari, R., Carr, R., Bell, A.S., Bartlett, E., Hutton, J.A., Llorian-Sopena, M., Chakravarty, P., Brzezicha, B., Janz, M., Garnett, M.J., Calado, D.P. and Tate, E.W.
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.
Keywords:	Animals, Mice
Source:	bioRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2021.03.20.436222
Date:	20 March 2021
Official Publication:	https://doi.org/10.1101/2021.03.20.436222

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