%0 Journal Article
%A Gámez-Chiachio, Manuel
%A Molina-Crespo, Ángela
%A Ramos-Nebot, Carmen
%A Martinez-Val, Jeannette
%A Martinez, Lidia
%A Gassner, Katja
%A Llobet, Francisco 
%A Soriano, Mario
%A Hernandez, Alberto
%A Cordani, Marco
%A Bernadó-Morales, Cristina
%A Diaz, Eva
%A Rojo-Sebastian, Alejandro
%A Triviño, Juan Carlos
%A Sanchez, Laura
%A Rodríguez-Barrueco, Ruth
%A Arribas, Joaquín
%A Llobet-Navás, David
%A Sarrió, David
%A Moreno Bueno, Gema
%T Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation
%D 2022
%@ 1756-9966
%U https://hdl.handle.net/20.500.14352/91630
%X 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.
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