Gámez-Chiachio, ManuelMolina-Crespo, ÁngelaRamos-Nebot, CarmenMartinez-Val, JeannetteMartinez, LidiaGassner, KatjaLlobet, Francisco J.Soriano, MarioHernandez, AlbertoCordani, MarcoBernadó Morales, CristinaDiaz, EvaRojo-Sebastian, AlejandroTriviño Salazar, Juan CarlosSánchez, LauraRodríguez-Barrueco, RuthArribas, JoaquínLlobet-Navas, DavidSarrió, DavidMoreno-Bueno, Gema2023-02-032023-02-032022Gámez-Chiachio M, Molina-Crespo Á, Ramos-Nebot C, Martinez-Val J, Martinez L, Gassner K, Llobet FJ, Soriano M, Hernandez A, Cordani M, Bernadó-Morales C, Diaz E, Rojo-Sebastian A, Triviño JC, Sanchez L, Rodríguez-Barrueco R, Arribas J, Llobet-Navás D, Sarrió D, Moreno-Bueno G. Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation. J Exp Clin Cancer Res. 2022 Sep 26;41(1):285. DOI: 10.1186/s13046-022-02497-w0392-9078http://hdl.handle.net/10230/55598Background: 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.application/pdfeng© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1186/s13046-022-02497-wAnti-HER2 therapyDrug resistanceGasdermin BGastroesophageal tumorsHER2 breast cancerLC3BProtective autophagyinfo:eu-repo/semantics/openAccess