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EGFRvIII tumorigenicity requires PDGFRA co-signaling and reveals therapeutic vulnerabilities in glioblastoma

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.

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Fig. 1: Canertinib treatments induce apoptosis in EGFRvIII GBM PDXs.
Fig. 2: Antigrowth efficacy of Canertinib in vivo.
Fig. 3: Canertinib treatment decreases the activity of PDGFRA and demonstrates dose-dependent antitumor activity.
Fig. 4: Simultaneous inhibition of MEK1/2 and PI3K signaling is necessary to trigger apoptosis in GBM6 PDX cells.
Fig. 5: Inhibition of PDGFRA sensitizes GBM PDX cells to EGFR inhibition.
Fig. 6: EGFRvIII expression requires co-signaling for cellular transformation in vitro and GBM tumor formation in vivo.
Fig. 7: PDGFRA activation cooperates with EGFRvIII to initiate GBM tumorigenesis in vivo.

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Acknowledgements

The authors thank Drs. Shruti Rawal and Shibani Mukherjee for critical review of the manuscript. The authors also thank Patrick Hyland (Tufts University), Ilyse Blazar (Boston University), Derrek Schartz (Tufts University) for their technical assistance. This work was supported by NIH grants R01 CA229784 and R21 CA245337 to AC and by internal funding to the Mayo Clinic GBM PDX National Resource to JNS.

Funding

This work was supported by NIH grants R01 CA229784 and R21 CA245337 to AC and by internal funding to the Mayo Clinic GBM PDX National Resource to JNS.

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Yeo, A.T., Jun, H.J., Appleman, V.A. et al. EGFRvIII tumorigenicity requires PDGFRA co-signaling and reveals therapeutic vulnerabilities in glioblastoma. Oncogene 40, 2682–2696 (2021). https://doi.org/10.1038/s41388-021-01721-9

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