EGFRvIII tumorigenicity requires PDGFRA co-signaling and reveals therapeutic vulnerabilities in glioblastoma.
Oncogene
; 40(15): 2682-2696, 2021 04.
Article
in En
| MEDLINE
| ID: mdl-33707748
ABSTRACT
Focal amplification of epidermal growth factor receptor (EGFR) and its ligand-independent, constitutively active EGFRvIII mutant form are prominent oncogenic drivers in glioblastoma (GBM). The EGFRvIII gene rearrangement is considered to be an initiating event in the etiology of GBM, however, the mechanistic details of how EGFRvIII drives cellular transformation and tumor maintenance remain unclear. Here, we report that EGFRvIII demonstrates a reliance on PDGFRA co-stimulatory signaling during the tumorigenic process in a genetically engineered autochthonous GBM model. This dependency exposes liabilities that were leveraged using kinase inhibitors treatments in EGFRvIII-expressing GBM patient-derived xenografts (PDXs), where simultaneous pharmacological inhibition of EGFRvIII and PDGFRA kinase activities is necessary for anti-tumor efficacy. Our work establishes that EGFRvIII-positive tumors have unexplored vulnerabilities to targeted agents concomitant to the EGFR kinase inhibitor repertoire.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Brain Neoplasms
/
Glioblastoma
/
Receptor, Platelet-Derived Growth Factor alpha
/
ErbB Receptors
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Oncogene
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2021
Document type:
Article
Affiliation country: