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- Title
Fatty acid synthase as a new therapeutic target for HER2-positive gastric cancer.
- 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.
- Abstract
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.
- Subjects
FATTY acid synthases; STOMACH cancer; CANCER cell culture; CANCER stem cells; MESSENGER RNA; CELL culture
- Publication
Cellular Oncology (2211-3428), 2023, Vol 46, Issue 3, p661
- ISSN
2211-3428
- Publication type
Article
- DOI
10.1007/s13402-023-00769-x