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| Página principal > Artículos > Artículos publicados > Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation |
(Vall d'Hebron Institut d'Oncologia) (Mecanismos Moleculares Y Terapia Experimental en Oncologia-Programa OncobellIdibell (L'Hospitalet de Llobregat)) (Universitat de Barcelona. Unitat d'Anatomia Humana i Embriologia) (Vall d'Hebron Institut d'Oncologia) (Fundación MD Anderson Internacional (Madrid))| Fecha: | 2022 |
| Resumen: | 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. 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. 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. 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. The online version contains supplementary material available at 10. 1186/s13046-022-02497-w. |
| Ayudas: | Agencia Estatal de Investigación PID2019-104644RB-I00 Ministerio de Economía y Competitividad CB16/12/00449 Ministerio de Economía y Competitividad CB16/12/00231 Ministerio de Economía y Competitividad CB16/12/00295 Instituto de Salud Carlos III PI19/01181 Instituto de Salud Carlos III PI18/00795 |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: | Anglès |
| Documento: | Article ; recerca ; Versió publicada |
| Materia: | Gasdermin B ; Protective autophagy ; Anti-HER2 therapy ; Drug resistance ; HER2 breast cancer ; Gastroesophageal tumors ; LC3B |
| Publicado en: | Journal of Experimental & Clinical Cancer Research : CR, Vol. 41 (september 2022) , ISSN 1756-9966 |
