Egfr ligand shifts the role of egfr from oncogene to tumor suppressor in egfr amplified glioblastoma

Abstract Glioblastoma (GBM) is a devastating cancer largely because of its highly invasive nature. Although pathways that promote GBM invasion have been identified, no pathway that actively suppresses GBM invasion is known and there is no treatment that specifically blocks GBM invasion. EGFR is a prime oncogene and is frequently amplified and mutated in GBM. However multiple clinical trials of EGFR inhibition in GBM have failed. Here, we demonstrate that EGFR ligands activate a tumor suppressor for the EGFR in EGFR-amplified GBMs. Analysis of TCGA data reveals that GBM patients with EGFR amplification and a low level of EGFR ligands have a worse prognosis compared to those with EGFR amplification and a high level of EGFR ligands. We identify the cytoskeletal BAR domain protein BIN3 as a critical suppressor of invasion upregulated by EGFR ligand in EGFR amplified GBMs. BIN3 inhibits a DOCK-7 Rho GTPase pathway, resulting in small hyper-proliferating noninvasive tumors and a better prognosis, while constitutive EGFR wild type or EGFRvIII signaling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumors and worse survival in orthotopic models. Consistent with its role as a negative regulator of invasion, BIN3 is deleted in 10% of GBMs and increased expression of BIN3 confers a better prognosis. Thus, increased EGFR ligand shifts the role of EGFR from oncogene to tumor suppressor in EGFR amplified GBMs by suppressing invasion. We identify tofacitinib, a BBB penetrant drug as an upregulator of BIN3 and show that tofacitinib suppresses invasion and prolongs survival in orthotopic models. Our study identifies a new tumor suppressive function of EGFR in GBM and we propose the use of tofacitinib to directly target invasion in EGFR-amplified and EGFR ligand-poor GBMs.