Fatty acid synthase as a new therapeutic target for HER2-positive gastric cancer

Purpose Trastuzumab is an HER2-specific agent approved as the gold-standard therapy for advanced HER2-positive (HER2+) gastric cancer (GC), but the high rate and rapid appearance of resistance limit its clinical efficacy, resulting in the need to identify new vulnerabilities. Defining the drivers in...

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Published in:Cellular oncology (Dordrecht) 2023-06, Vol.46 (3), p.661-676
Main Authors: Castagnoli, Lorenzo, Corso, Simona, Franceschini, Alma, Raimondi, Alessandra, Bellomo, Sara Erika, Dugo, Matteo, Morano, Federica, Prisciandaro, Michele, Brich, Silvia, Belfiore, Antonino, Vingiani, Andrea, Di Bartolomeo, Maria, Pruneri, Giancarlo, Tagliabue, Elda, Giordano, Silvia, Pietrantonio, Filippo, Pupa, Serenella M.
Format: Article
Language:English
Subjects:
Animals
Biomedical and Life Sciences
Biomedicine
Cancer Research
Cell Line, Tumor
Cell survival
ErbB-2 protein
Fatty Acid Synthases - metabolism
Fatty Acid Synthases - therapeutic use
Fatty acids
Fatty-acid synthase
Flow cytometry
Gastric cancer
Medical prognosis
Mice
Oncology
Pathology
Receptor, ErbB-2 - metabolism
Stomach Neoplasms - pathology
Therapeutic targets
Transcriptomes
Trastuzumab
Trastuzumab - pharmacology
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Summary:Purpose Trastuzumab is an HER2-specific agent approved as the gold-standard therapy for advanced HER2-positive (HER2+) gastric cancer (GC), but the high rate and rapid appearance of resistance limit its clinical efficacy, resulting in the need to identify new vulnerabilities. Defining the drivers influencing HER2+ cancer stem cell (CSC) maintenance/survival could represent a clinically useful strategy to counteract tumor growth and therapy resistance. Accumulating evidence show that targeting crucial metabolic hubs, as the fatty acid synthase (FASN), may be clinically relevant. Methods FASN protein and transcript expression were examined by WB and FACS and by qRT-PCR and GEP analyses, respectively, in trastuzumab-sensitive and trastuzumab-resistant HER2+ GC cell lines cultured in adherent (2D) or gastrosphere promoting (3D) conditions. Molecular data were analyzed in silico in public HER2+ GC datasets. The effectiveness of the FASN inhibitor TVB3166 to overcome anti-HER2 therapy resistance was tested in vitro in gastrospheres forming efficiency bioassays and in vivo in mice bearing trastuzumab-resistant GC cells. Results We compared the transcriptome profiles of HER2+ GC cells cultured in 2D versus 3D conditions finding a significant enrichment of FASN in 3D cultures. FASN upregulation significantly correlated with high stemness score and poor prognosis in HER2+ GC cases. TVB3166 treatment significantly decreased GCSCs in all cell targets. HER2 and FASN cotargeting significantly decreased the capability to form gastrospheres versus monotherapy and reduced the in vivo growth of trastuzumab-resistant GC cells. Conclusion Our findings indicate that cotargeting HER2 and FASN increase the benefit of anti-HER2 therapy representing a new opportunity for metabolically combating trastuzumab-resistant HER2+ GC.
ISSN:2211-3428
2211-3436
DOI:10.1007/s13402-023-00769-x