Details

Autor(en) / Beteiligte

• De Bacco, Francesca
• Orzan, Francesca
• Erriquez, Jessica
• Casanova, Elena
• Barault, Ludovic
• Albano, Raffaella
• D’Ambrosio, Antonio
• Bigatto, Viola
• Reato, Gigliola
• Patanè, Monica
• Pollo, Bianca
• Kuesters, Geoffrey
• Dell’Aglio, Carmine
• Casorzo, Laura
• Pellegatta, Serena
• Finocchiaro, Gaetano
• Comoglio, Paolo M.
• Boccaccio, Carla

Titel

ERBB3 overexpression due to miR-205 inactivation confers sensitivity to FGF, metabolic activation, and liability to ERBB3 targeting in glioblastoma

Ist Teil von

• Cell reports (Cambridge), 2021-07, Vol.36 (4), p.109455-109455, Article 109455

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy. [Display omitted] •Total of ∼9% of human GBMs feature ERBB3 overexpression and nuclear accumulation•ERBB3 overexpression is sustained by miR-205 inactivation•Overexpressed ERBB3 is activated by FGFR and upregulates cell metabolism•ERBB3 targeting by a specific antibody inhibits growth of ERBB3-overexpressing GBMs Taking advantage of an integrated model based on patient-derived stem-like cells, De Bacco et al. identify a GBM subset characterized by ERBB3 overexpression, driven by an inheritable mechanism of miR-205 inactivation. By upregulating cell metabolism, overexpressed ERBB3 provides a selective advantage and a liability to be exploited for targeted therapy.