Amazing work! Congratulations!

Congratulations to first authors Gregor Lueg, James Zhang, Monica Faronato and big thanks to all co-authors for being amazing colleagues and collaborators!

Special thanks to Ed Tate and Dinis Calado for supervising this exciting project!

Finally, we show that an orally bioavailable NMTi eliminates MYC-deregulated tumours in vivo without overt toxicity. MYC oncogene is deregulated in >50% of cancers but is notoriously difficult to target. Our discovery of the MYC-NMTi synthetic lethality circumvents this obstacle.

Fortuitously, we discover that a patient mutation in NDUFAF4, associated with a neurological disorder called the Leigh syndrome, also leads to loss of myristoylation on NDUFAF4, its degradation and therefore dysfunctional respiratory complex I.

Mechanistically, NMTi-induced mitochondrial failure is concurrent with loss of myristoylation on respiratory complex I assembly factor NDUFAF4 with its subsequent proteasomal degradation via the glycine N-degron mechanism.

Using proteomics, we discovered that NMTi cause mitochondrial dysfunction (complex I defects) in high-MYC cancer cells.

We screened hundreds of cancer cell lines using a potent and selective N-myristoyltransferase inhibitor (NMTi) and found a strong correlation between increased NMTi sensitivity and MYC deregulation with death of high (vs low) MYC cancer cells.

Big thanks to all co-authors at FGC in Cambridge, Hull, Oslo, NCI Frederick and of course @ahellab.bsky.social @dunnschool.bsky.social! I had a lot of fun doing proteomics in Steve Gygi’s lab @harvardcellbio.bsky.social funded by Sir Henry Wellcome Fellowship - thanks to @wellcometrust.bsky.social!

Plus, our CRISPR screen identified SOCS3 knockout as a new synthetic lethal interaction with PARP7i. Curiously, SOCS3 is also linked to AHR signalling.