Please use this identifier to cite or link to this item:
Title: Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation
Author: Gámez-Chiachio, Manuel
Molina-Crespo, Ángela
Ramos-Nebot, Carmen
Martinez-Val, Jeannette
Martínez, Lídia
Gassner, Katja
Llobet, Francisco J.
Soriano, Mario
Hernandez, Alberto
Cordani, Marco
Bernadó-Morales, Cristina
Diaz, Eva
Rojo-Sebastian, Alejandro
Triviño, Juan Carlos
Sanchez, Laura
Rodriguez Barrueco, Ruth
Arribas, Joaquín
Llobet-Navas, David
Sarrió, David
Moreno-Bueno, Gema
Keywords: Càncer de mama
Resistència als medicaments
Breast cancer
Drug resistance
Issue Date: 26-Sep-2022
Publisher: BioMed Central
Abstract: Background: Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel efective targeted treatments for HER2/GSDMB aggressive tumors. Methods: Diferent in vitro approaches (immunoblot, qRT-PCR, fow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. Results: GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafsh and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates signifcantly with relapse in HER2 breast and gastric cancers. Conclusion: Our fndings uncover for the frst time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB+cancers with adverse clinical outcome.
Note: Reproducció del document publicat a:
It is part of: Journal of Experimental & Clinical Cancer Research, 2022, vol. 41, num. 1, p. 285
Related resource:
ISSN: 1756-9966
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Patologia i Terapèutica Experimental)

Files in This Item:
File Description SizeFormat 
725910.pdf9.84 MBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons