RT Journal Article
T1 Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation
A1 Gámez-Chiachio, Manuel
A1 Molina-Crespo, Ángela
A1 Ramos-Nebot, Carmen
A1 Martinez-Val, Jeannette
A1 Martinez, Lidia
A1 Gassner, Katja
A1 Llobet, Francisco
A1 Soriano, Mario
A1 Hernandez, Alberto
A1 Cordani, Marco
A1 Bernadó-Morales, Cristina
A1 Diaz, Eva
A1 Rojo-Sebastian, Alejandro
A1 Triviño, Juan Carlos
A1 Sanchez, Laura
A1 Rodríguez-Barrueco, Ruth
A1 Arribas, Joaquín
A1 Llobet-Navás, David
A1 Sarrió, David
A1 Moreno Bueno, Gema
AB 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 effective targeted treatments for HER2/GSDMB aggressive tumors.Methods: Different in vitro approaches (immunoblot, qRT-PCR, flow 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 zebrafish 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 significantly with relapse in HER2 breast and gastric cancers.Conclusion: Our findings uncover for the first 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.
PB Springer
SN 1756-9966
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/91630
UL https://hdl.handle.net/20.500.14352/91630
LA eng
NO Gámez-Chiachio, M., Molina-Crespo, Á., Ramos-Nebot, C. et al. Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation. J Exp Clin Cancer Res 41, 285 (2022). https://doi.org/10.1186/s13046-022-02497-w
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Instituto de Salud Carlos III
NO Asociación Española Contra el Cancer
NO Breast Cancer Research Foundation
NO Generalitat de Catalunya
NO Centro de Investigación Biomédica en Red 
NO European Commission
DS Docta Complutense
RD 24 abr 2025