Abstract 942: ErbB3 overexpression unleashed by miR-205 epigenetic silencing is a therapeutic target in glioblastoma

Abstract

Abstract In glioblastoma (GBM), the most frequent and lethal brain tumor, targeted therapies suppressing commonly altered signaling pathways has remained so far disappointing. However, in selected patient subsets, specific genetic alterations can confer sensitivity to targeted agents. In this study, by generating an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, we identified a human GBM subset (around 9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. This was driven by inheritable epigenetic or post-transcriptional silencing of the oncosuppressor miR-205 and sustained the malignant phenotype. Unexpectedly, ERBB3, known to be devoid of autonomous signaling properties, was overexpressed in the absence of the other members of the EGFR family, but behaved as a specific signaling platform for FGFRs. ERBB3/FGFR dimerization led to hyperactivation of the PI3K/AKT/mTOR pathway and consequent upregulation of glycolysis, oxidative metabolism and de novo fatty acid biosynthesis. Treatment with a specific antibody (MM121) preventing ERBB3 association with FGFR caused metabolic shutdown and consequent proliferative arrest and apoptosis induction in vitro. Moreover, experimental tumors regenerated through ERBB3 overexpressing stem-like cell transplantation reproduced the features of the original GBMs and, upon treatment with the anti-ERBB3 antibody, significantly regressed. These findings identify a subset of GBM patients where exploitation of an ERBB3-targeted therapy could be effective. Citation Format: Francesca De Bacco, Francesca Orzan, Jessica Erriquez, Elena Casanova, Ludovic Barault, Raffaella Albano, Antonio D'Ambrosio, Viola Bigatto, Gigliola Reato, Monica Patané, Bianca Pollo, Geoffrey Kuesters, Carmine Dell'Aglio, Laura Casorzo, Serena Pellegatta, Gaetano Finocchiaro, Paolo M. Comoglio, Carla Boccaccio. ErbB3 overexpression unleashed by miR-205 epigenetic silencing is a therapeutic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 942.