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PurposeGasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing cell invasion, metastasis and 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.Experiment designTo decipher the functional relevance of GSDMB in promoting resistance to HER2-targeted therapies we performed several molecular approaches (immunoblot, qRT-PCR, flow cytometry, immunoprecipitation and confocal microscopy) in different breast and gastric carcinoma cell models. The results were confirmed in Patient Derived Xenografts (PDX) by qRT-PCR and in clinical human cancer samples by immunohistochemistry. Finally, we validated the efficacy of the identified targeted treatment in HER2/GSDMB cancers using two complementary in vivo preclinical models (tumor xenografts in mice and zebrafish).ResultsWe discovered that GSDMB up-regulation renders HER2 breast and gastric cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Consistent with this, we proved that the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response specifically in GSDMB-positive tumors in vitro and in vivo using zebrafish and mice preclinical cancer models. Mechanistically, we confirmed that the GSDMB N-terminal domain interacts with the autophagy protein LC3B. Finally, we validated these results in clinical samples of breast and gastric cancers, where GSDMB/LC3B co-expression associates significantly with relapse.ConclusionOur findings uncovered a novel functional link between GSDMB over-expression and LC3B-mediated protective autophagy in response to HER2-targeted therapies and provide a new and accessible therapeutic approach for HER2/GSDMB+ cancers with adverse clinical outcome.TRANSLATIONAL RELEVANCEIdentifying the biomarkers and mechanisms of therapy resistance is a main challenge in current oncology. In this regard, Gasdermin-B (GSDMB) over-expression, which was initially found in >60% HER2 breast cancers, promotes resistance to therapy through an unknown molecular mechanism. In the present work, we revealed for the first time that in HER2 gastric and breast cancers GSDMB mediates innate and acquired resistance to HER2-targeted drugs through the promotion of a pro-survival autophagy mechanism that requires the interaction of GSDMB with LC3B. Accordingly, GSDMB/LC3B co-expression in human breast and gastric cancer clinical samples associates with relapse. To reverse this anti-drug effect, we developed a therapeutic approach based on the combination of the autophagy inhibitor chloroquine with lapatinib that showed significant efficacy both in vitro and in vivo on GSDMB-positive tumors. Our findings provide an accessible (FDA-approved drugs) therapeutic combination to treat effectively HER2/GSDMB over-expressing tumors with poor clinical outcome.