ABHD17 enzymes regulate dynamic plasma membrane palmitoylation and N-Ras-dependent cancer growth [@MJNiphakis]

Jarrett R Remsberg, Radu M Suciu, Noemi A Zambetti, Thomas W Hanigan, Ari J Firestone, Anagha Inguva, Amy Long, Nhi Ngo, Kenneth M Lum, Cassandra L Henry, Stewart K Richardson, Marina Predovic, Ben Huang, Amy R Howell, Micah J Niphakis, Kevin Shannon, Benjamin F Cravatt
bioRxiv, 2020
 doi: https://doi.org/10.1101/2020.05.21.108316

A subset of Ras proteins, including N-Ras, depend on a palmitoylation/depalmitoylation cycle to regulate their subcellular trafficking and oncogenicity. General lipase inhibitors such as Palmostatin M block N-Ras depalmitoylation, but lack specificity and target several enzymes displaying depalmitoylase activity. Here, we describe ABD957, a potent and selective covalent inhibitor of the ABHD17 family of depalmitoylases, and show that this compound impairs N-Ras depalmitoylation in human acute myeloid leukemia (AML) cells. ABD957 produced partial effects on N-Ras palmitoylation compared to Palmostatin M, but was much more selective across the proteome, reflecting a plasma membrane-delineated action on dynamically palmitoylated proteins. Finally, ABD957 impaired N-Ras signaling and the growth of NRAS-mutant AML cells in a manner that synergizes with MEK inhibition. Our findings uncover a surprisingly restricted role for ABHD17 enzymes in modulating the N-Ras palmitoylation cycle and suggest that ABHD17 inhibitors may have value as targeted therapies for NRAS-mutant cancers

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