ABHD17 regulation of plasma membrane palmitoylation and N-Ras-dependent cancer growth

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Ras proteins, including N-Ras, rely on palmitoylation/depalmitoylation for function and oncogenic potential.
• Existing inhibitors like Palmostatin M lack specificity, affecting multiple depalmitoylases.
• Selective targeting of depalmitoylases is crucial for understanding N-Ras regulation and developing cancer therapies.

Purpose of the Study:

• To introduce and characterize ABD957, a selective inhibitor of the ABHD17 family of depalmitoylases.
• To investigate the effects of ABD957 on N-Ras depalmitoylation and signaling in acute myeloid leukemia (AML) cells.
• To evaluate the therapeutic potential of ABHD17 inhibition in NRAS-mutant AML.

Main Methods:

• Utilized ABD957, a selective covalent inhibitor of ABHD17 depalmitoylases.
• Assessed N-Ras depalmitoylation and palmitoylation in human AML cells.
• Compared the selectivity and effects of ABD957 with Palmostatin M.
• Evaluated N-Ras signaling pathways and cell growth inhibition in NRAS-mutant AML cells, including combination therapy with MEK inhibitors.

Main Results:

• ABD957 effectively impaired N-Ras depalmitoylation in AML cells.
• ABD957 demonstrated higher selectivity across the proteome compared to Palmostatin M.
• The compound showed plasma membrane-localized effects on dynamically palmitoylated proteins.
• ABD957 inhibited N-Ras signaling and NRAS-mutant AML cell growth, synergizing with MEK inhibition.

Conclusions:

• ABHD17 enzymes play a specific role in regulating the N-Ras palmitoylation cycle.
• ABD957 is a potent and selective inhibitor with potential applications in targeted cancer therapy.
• ABHD17 inhibitors represent a promising therapeutic strategy for NRAS-mutant cancers, particularly in combination with MEK inhibitors.