Targeting fatty acid synthase suppresses tumor development in NF2/CDKN2A-deficient pleural mesothelioma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Pleural mesothelioma (PM) is a rare but aggressive cancer often linked to asbestos exposure.
• Current treatments for PM have limited efficacy, leading to poor patient prognosis.
• Identifying novel molecular targets is crucial for developing more effective PM therapies.

Purpose of the Study:

• To identify a novel molecular target inhibitor for developing improved therapeutics for pleural mesothelioma.
• To evaluate the efficacy of cerulenin, a fatty acid synthase (FASN) inhibitor, against PM cells.

Main Methods:

• Drug screening assays were performed to assess the antiproliferative effects of cerulenin and other agents on PM cells.
• FASN protein expression was analyzed in patient-derived PM tissues with varying NF2/CDKN2A(p16) statuses.
• Tumor growth was evaluated in xenograft mouse models following cerulenin administration.
• The effect of cerulenin on mitochondrial dynamics and DRP1 ubiquitination was investigated in PM cells.

Main Results:

• Cerulenin demonstrated potent and selective antiproliferative activity against NF2/CDKN2A(p16)-deficient PM cells.
• FASN protein was highly expressed in NF2/p16-deficient PM tumors but rarely in NF2/p16-intact tumors.
• Cerulenin treatment significantly inhibited the growth of NF2/p16-deficient PM tumors in vivo.
• Cerulenin was found to inhibit mitochondrial fission by targeting DRP1, and FASN gene disruption increased DRP1 ubiquitination.

Conclusions:

• Fatty acid synthase (FASN) is a potential therapeutic target in NF2/p16-deficient pleural mesothelioma.
• Cerulenin's ability to inhibit FASN and modulate mitochondrial dynamics presents a novel therapeutic strategy.
• These findings open new possibilities for precision medicine approaches in treating PM.