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EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.

ABSTRACT: The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3.

SUBMITTER: Guo G

PROVIDER: S-EPMC9389625 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.

Guo Gao G Gong Ke K Beckley Nicole N Zhang Yue Y Yang Xiaoyao X Chkheidze Rati R Hatanpaa Kimmo J KJ Garzon-Muvdi Tomas T Koduru Prasad P Nayab Arifa A Jenks Jennifer J Sathe Adwait Amod AA Liu Yan Y Xing Chao C Wu Shwu-Yuan SY Chiang Cheng-Ming CM Mukherjee Bipasha B Burma Sandeep S Wohlfeld Bryan B Patel Toral T Mickey Bruce B Abdullah Kalil K Youssef Michael M Pan Edward E Gerber David E DE Tian Shulan S Sarkaria Jann N JN McBrayer Samuel K SK Zhao Dawen D Habib Amyn A AA

Nature cell biology 20220801 8

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating B ...[more]

PMID: 35915159

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Project description:BackgroundThe treatment efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors like erlotinib has not met expectations for glioblastoma therapy, even for EGFR-overexpressing tumors. We determined possible mechanisms of therapy resistance using the unique BS153 glioblastoma cell line, which has retained amplification of the egfr gene and expression of EGFR variant (v)III.MethodsFunctional effects of erlotinib, gefitinib, and cetuximab on BS153 proliferation, migration, and EGFR-dependent signal transduction were systematically compared in vitro. The tumor-initiating capacity of parental and treatment-resistant BS153 was studied in Naval Medical Research Institute/Foxn1(nu) mice. Potential mediators of resistance were knocked down using small interfering (si)RNA.ResultsErlotinib and gefitinib inhibited proliferation and migration of BS153 in a dose-dependent manner, whereas cetuximab had no effect. BS153 developed resistance to erlotinib (BS153(resE)) but not to gefitinib. Resistance was associated with strong upregulation of EGFRvIII and subsequent activation of the phosphatidylinositol-3-OH kinase (PI3K) pathway in BS153(resE) and an increased expression of the regulatory 110-kDa delta subunit of PI3K (p110δ). Knockdown of EGFRvIII in BS153(resE) largely restored sensitivity to erlotinib. Targeting PI3K pharmacologically caused a significant decrease in cell viability, and specifically targeting p110δ by siRNA partially restored erlotinib sensitivity in BS153(resE). In vivo, BS153 formed highly invasive tumors with an unusual growth pattern, displaying numerous satellites distant from the initial injection site. Erlotinib resistance led to delayed onset of tumor growth as well as prolonged overall survival of mice without changing tumor morphology.ConclusionsEGFRvIII can mediate resistance to erlotinib in EGFR-amplified glioblastoma via an increase in PI3Kp110δ. Interfering with PI3Kp110δ can restore sensitivity toward the tyrosine kinase inhibitor.

Dataset Information

EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.

Publications

EGFR ligand shifts the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation.

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