Fatty acid synthase as a new therapeutic target for HER2-positive gastric cancer
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Published:2023-02-08
Issue:3
Volume:46
Page:661-676
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ISSN:2211-3428
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Container-title:Cellular Oncology
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language:en
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Short-container-title:Cell Oncol.
Author:
Castagnoli LorenzoORCID, Corso SimonaORCID, Franceschini AlmaORCID, Raimondi AlessandraORCID, Bellomo Sara ErikaORCID, Dugo MatteoORCID, Morano FedericaORCID, Prisciandaro Michele, Brich SilviaORCID, Belfiore AntoninoORCID, Vingiani AndreaORCID, Di Bartolomeo MariaORCID, Pruneri GiancarloORCID, Tagliabue EldaORCID, Giordano SilviaORCID, Pietrantonio FilippoORCID, Pupa Serenella M.ORCID
Abstract
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.
Funder
Fondazione Pezcoller Associazione Italiana per la Ricerca sul Cancro
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine,General Medicine
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