Human N-myristoyltransferase (NMT) 1 and 2 catalyze N-terminal protein myristoylation, a modification that regulates membrane trafficking and interactions of >100 proteins. NMT has been proposed as a target in cancer, but a rationale for selectivity is lacking due to the complex impact of NMT inhibition (NMTi) on multiple cellular pathways. Here, large-scale screens of hundreds of cancer cell lines against a panel of potent and selective NMTi were combined with systems-level analyses to reveal that NMTi is synthetically lethal with deregulated MYC or MYCN. Synthetic lethality is mediated by post-transcriptional failure in (NADH) Complex I protein synthesis followed by mitochondrial dysfunction in MYC-deregulated cancer cells. We observed that NMT inhibitors blocked the growth of patient-derived tumors with deregulated MYC, without overt toxicity. This mechanistic framework supports NMTi as a novel targeted therapeutic approach and provides a new paradigm in which targeting of a constitutive protein modification is synthetically lethal in MYC-deregulated cancers.

Citation Format: Gregor A. Lueg, Monica Faronato, Andrii Gorelik, Andrea G. Grocin, Miriam Llorian-Sopena, Probir Chakravarty, Bernadette Brzezicha, Martin Janz, Mathew J. Garnett, Dinis P. Calado, Edward W. Tate. Targeting MYC deregulation in cancer [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA30.