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

Item Type:Preprint
Title:N-myristoyltransferase inhibition is synthetic lethal in MYC-deregulated cancers
Creators Name:Lueg, G.A. and Faronato, M. and Gorelik, A. and Grocin, A.G. and Caamano-Gutierrez, E. and Falciani, F. and Solari, R. and Carr, R. and Bell, A.S. and Bartlett, E. and Hutton, J.A. and Llorian-Sopena, M. and Chakravarty, P. and Brzezicha, B. and Janz, M. and Garnett, M.J. and 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
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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