ERBB3 overexpression due to miR-205 inactivation confers sensitivity to FGF, metabolic activation, and liability to ERBB3 targeting in glioblastoma
Francesca De Bacco,
Francesca Orzan,
Jessica Erriquez,
Elena Casanova,
Ludovic Barault,
Raffaella Albano,
Antonio D’Ambrosio,
Viola Bigatto,
Gigliola Reato,
Monica Patanè,
Bianca Pollo,
Geoffrey Kuesters,
Carmine Dell’Aglio,
Laura Casorzo,
Serena Pellegatta,
Gaetano Finocchiaro,
Paolo M. Comoglio,
Carla Boccaccio
Affiliations
Francesca De Bacco
Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Francesca Orzan
Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Jessica Erriquez
Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Elena Casanova
Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Ludovic Barault
Laboratory of Cancer Epigenetics, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy; Department of Oncology, University of Torino Medical School, 10060 Candiolo, Turin, Italy
Raffaella Albano
Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Antonio D’Ambrosio
Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Viola Bigatto
Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Gigliola Reato
Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Monica Patanè
Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milan, Italy
Bianca Pollo
Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milan, Italy
Geoffrey Kuesters
Merrimack Pharmaceuticals, Inc., One Broadway, 14th floor, Cambridge, MA 02142, USA
Carmine Dell’Aglio
Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy; Santa Croce e Carle Hospital, 12100 Cuneo, Italy
Laura Casorzo
Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy
Serena Pellegatta
Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milan, Italy
Gaetano Finocchiaro
Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milan, Italy; Department of Neurology, IRCCS Ospedale San Raffaele, 20132, Milan, Italy
Paolo M. Comoglio
Laboratory of Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy; IFOM, FIRC Institute of Molecular Oncology, 20139 Milan, Italy
Carla Boccaccio
Laboratory of Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, 10060 Candiolo, Turin, Italy; Department of Oncology, University of Torino Medical School, 10060 Candiolo, Turin, Italy; Corresponding author
Summary: 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.
