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 Gassner, Katja
A1 Llobet, Francisco Javier
A1 Soriano, Mario
A1 Hernández, Alberto
A1 Cordan, Marco
A1 Bernadó Morales, Cristina
A1 Díaz, Eva
A1 Rojo-Sebastián, Alejandro
A1 Triviño-Salazar, Juan Carlos
A1 Sánchez, Laura
A1 Rodríguez-Barrueco, Ruth
A1 Arribas, Joaquín
A1 Llobet-Navá, David
A1 Sarrió, David
A1 Moreno-Bueno, Gema
A1 Martínez, Lidia
K1 Gasdermin B
K1 Protective autophagy
K1 Anti-HER2 therapy
K1 Drug resistance
K1 HER2 breast cancer
K1 Gastroesophageal tumors
K1 LC3B
AB BackgroundGasdermin 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.MethodsDifferent 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.ResultsGSDMB 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.ConclusionOur 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 Nature
PB BioMed Central
YR 2022
FD 2022-09-26
LK http://hdl.handle.net/10347/32321
UL http://hdl.handle.net/10347/32321
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 This study has been supported by the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (PID2019-104644RB-I00) -GMB-, the Instituto de Salud Carlos III (CIBERONC, CB16/12/00449 -JA-, CB16/12/00231 -DLN- and CB16/12/00295 -GMB-, PI19/01181 -JA-, PI18/00795, CP17/00063 and RTI2018-095611-A-I00 -DLN- and ERA-NET TRANSCAN-2 -JA- [all partly supported by FEDER funds]) and by the AECC Scientific Foundation (FC_AECC PROYE19036MOR -GMB- and LABAE19004LLOB -DLN-). Furthermore, this work was supported by Breast Cancer Research Foundation (BCRF-19–08) -JA-. We are also grateful to the CERCA Programme (Generalitat de Catalunya) for institutional support. MGC and DS contracts are funded by CIBERONC, KG is a recipient of a PFIS fellowship (FI19/00188), RRB is recipient of a Ramón y Cajal grant (RyC-2016–19671) and DLN is recipient of a Miguel Servet grant (MS17/00063) (all partly supported by FEDER funds). We are also grateful to MD Anderson BIOBANK for providing tumor samples. The bank (reference # B.0000745) belongs to the National Registry of Biobanks coordinated by the Carlos III Health Institute.
DS Minerva
RD 23 abr 2026