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Título

Intracellular delivery of an antibody targeting gasdermin-b reduces her2 breast cancer aggressiveness

AutorMolina-Crespo, Ángela; Cadete, Ana; Sarrió, David CSIC ORCID; Gamez-Chiachio, Manuel CSIC ORCID; Martínez Sánchez, Lidia CSIC; Chao, Kinlin; Olivera, Ana; Gonella, Andrea; Díaz, Eva; Palacios, José; Dhal, Pradeep K.; Besev, Magnus; Rodríguez-Serrano, Macarena; García-Bermejo, María Laura; Triviño, Juan Carlos; Cano, Amparo CSIC; García-Fuentes, Marcos; Herzberg, Osnat; Torres, Dolores; Alonso, María José; Moreno-Bueno, Gema CSIC ORCID
Fecha de publicación1-ago-2019
EditorAmerican Association for Cancer Research
CitaciónClinical Cancer Research 25(15): 4846-4858 (2019)
Resumen[Purpose]: Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers. Experimental Design: We have developed a new targeted nanomedicine based on hyaluronic acid–biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo.
[Results]: Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB.
[Conclusions]: Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.
Descripción© 2019 American Association for Cancer Research.
Versión del editorhttp://dx.doi.org/10.1158/1078-0432.CCR-18-2381
URIhttp://hdl.handle.net/10261/206891
DOI10.1158/1078-0432.CCR-18-2381
ISSN1078-0432
E-ISSN1557-3265
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