Repositioning Lomitapide to block ZDHHC5-dependant palmitoylation on SSTR5 leads to anti-proliferation effect in preclinical pancreatic cancer models

Palmitoylation of proteins plays important roles in various physiological processes, such as cell proliferation, inflammation, cell differentiation etc. However, inhibition of protein palmitoylation has led to few new drugs to date. ZDHHC5 serves as a key enzyme to catalyze palmitoylation on SSTR5 (a proven anti-proliferation receptor in pancreatic cells). Herein, we compare single-cell transcriptome data between pancreatic cancer tissues and normal pancreas tissues and identify that ZDHHC5 is a potential target to inhibit proliferation of pancreatic cancer cells. In addition, we report the repositioning of an orphan drug (Lomitapide) as an inhibitor of ZDHHC5, and we speculate that this inhibitor may be able to block palmitylation on SSTR5. Pharmacological blockade of ZDHHC5 with Lomitapide results in attenuated cancer cell growth and proliferation which collectively contributes to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of ZDHHC5 in pancreatic cancer, representing a new class of palmitoylation targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell palmitoylation.

Automated summary

Protein palmitoylation is important in various physiological processes, but few drugs targeting this process have been developed. This study identifies ZDHHC5 as a potential target for inhibiting pancreatic cancer cell proliferation through analysis of single-cell transcriptome data. The orphan drug Lomitapide is repurposed as an inhibitor of ZDHHC5, leading to attenuated cancer cell growth and proliferation. This study demonstrates the potential of ZDHHC5 as a therapeutic target in pancreatic cancer and lays the foundation for paradigm-shifting therapies targeting cancer cell palmitoylation.