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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.

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

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  • Medientyp: E-Artikel
  • Titel: Fatty acid synthase as a new therapeutic target for HER2-positive gastric cancer
  • Beteiligte: 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.
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: Cellular Oncology
  • Sprache: Englisch
  • DOI: 10.1007/s13402-023-00769-x
  • ISSN: 2211-3428; 2211-3436
  • Schlagwörter: Cancer Research ; Oncology ; Molecular Medicine ; General Medicine
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Purpose</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>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.</jats:p> </jats:sec>