Intracellular delivery of an antibody targeting Gasdermin-B reduces HER2 breast cancer aggressiveness.

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TitleIntracellular delivery of an antibody targeting Gasdermin-B reduces HER2 breast cancer aggressiveness.
Publication TypeJournal Article
Year of Publication2019
AuthorsMolina-Crespo, A, Cadete, A, Sarrio, D, Gamez-Chiachio, M, Martinez, L, Chao, K, Olivera, A, Gonella, A, Diaz, E, Palacios, J, Dhal, PK, Besev, M, Rodriguez-Serrano, M, García-Bermejo, MLaura, Triviño, JCarlos, Cano, A, Garcia-Fuentes, M, Herzberg, O, Torres, D, Alonso, MJose, Moreno-Bueno, G
JournalClin Cancer Res
Date Published2019 May 07
ISSN1078-0432
Abstract

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: a) lowering the in vitro cell migration induced by GSDMB; b) enhancing the sensitivity to trastuzumab; c) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and d) 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 pro-cell death activity of GSDMB.

CONCLUSION: 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 pro-tumor 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.

DOI10.1158/1078-0432.CCR-18-2381
Alternate JournalClin. Cancer Res.
PubMed ID31064780