Dataset Information

Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine Kinase Inhibitors in a Biomaterial Model of Glioblastoma.

ABSTRACT: 3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified in 50% of GBM patients. Here, hyaluronic acid (HA) decorated methacrylamide-functionalized gelatin (GelMA) hydrogels are used to examine the synergies between microenvironmental factors and a model EGFR tyrosine kinase inhibitor (TKI) using patient-derived xenograft cells. The in vitro behavior of 3 patient-derived xenografts that reflect a clinically relevant range of EGFR variants is characterized: GBM10 (EGFR, wild type), GBM12 (EGFR+), and GBM6 (EGFRvIII). GelMA hydrogels support xenograft culture; cells remain viable, active, respond to matrix-immobilized HA, and upregulate genes associated with matrix remodeling and tumor growth. Interestingly, matrix-immobilized HA alters the response of GBM cells to a model tyrosine kinase inhibitor, erlotinib. While constitutively activated EGFRvIII cells are sensitive to TKI in gelatin hydrogels, hyaluronic acid mediated adhesive signaling interacts with EGFRvIII signaling to increase cell metabolic activity, increase soluble hyaluronic acid synthesis, and modify response to erlotinib exposure.

SUBMITTER: Pedron S

PROVIDER: S-EPMC5726872 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine Kinase Inhibitors in a Biomaterial Model of Glioblastoma.

Pedron Sara S Hanselman Jacob S JS Schroeder Mark A MA Sarkaria Jann N JN Harley Brendan A C BAC

Advanced healthcare materials 20170802 21

3D biomaterial models have potential to explore the influence of the tumor microenvironment on aberrant signaling pathways and compensatory signals using patient-derived cells. Glioblastoma (GBM) tumors are highly heterogeneous, with both cell composition and extracellular matrix biophysical factors seen as key regulators of malignant phenotype and treatment outcomes. Amplification, overexpression, and mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase have been identified i ...[more]

PMID: 28766870

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Project description:Asparagine (N)-linked glycosylation is a posttranslational modification essential for the function of complex transmembrane proteins. However, targeting glycosylation for cancer therapy has not been feasible due to generalized effects on all glycoproteins. Here, we perform sensitivity screening of 94 lung cancer cell lines using NGI-1, a small-molecule inhibitor of the oligosaccharyltransferase (OST) that partially disrupts N-linked glycosylation, and demonstrate a selective loss of tumor cell viability. This screen revealed NGI-1 sensitivity in just 11 of 94 (12%) cell lines, with a significant correlation between OST and EGFR inhibitors. In EGFR-mutant non-small cell lung cancer with EGFR tyrosine kinase inhibitor (TKI) resistance (PC9-GR, HCC827-GR, and H1975-OR), OST inhibition maintained its ability to induce cell-cycle arrest and a proliferative block. Addition of NGI-1 to EGFR TKI treatment was synthetic lethal in cells resistant to gefitinib, erlotinib, or osimertinib. OST inhibition invariably disrupted EGFR N-linked glycosylation and reduced activation of receptors either with or without the T790M TKI resistance mutation. OST inhibition also dissociated EGFR signaling from other coexpressed receptors like MET via altered receptor compartmentalization. Translation of this approach to preclinical models was accomplished through synthesis and delivery of NGI-1 nanoparticles, confirmation of in vivo activity through molecular imaging, and demonstration of significant tumor growth delay in TKI-resistant HCC827 and H1975 xenografts. This therapeutic strategy breaks from kinase-targeted approaches and validates N-linked glycosylation as an effective target in tumors driven by glycoprotein signaling.Significance:EGFR-mutant NSCLC is incurable despite the marked sensitivity of these tumors to EGFR TKIs. These findings identify N-linked glycosylation, a posttranslational modification common to EGFR and other oncogenic signaling proteins, as an effective therapeutic target that enhances tumor responses for EGFR-mutant NSCLC. Cancer Res; 78(17); 5094-106. ©2018 AACR.

Dataset Information

Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine Kinase Inhibitors in a Biomaterial Model of Glioblastoma.

Publications

Extracellular Hyaluronic Acid Influences the Efficacy of EGFR Tyrosine Kinase Inhibitors in a Biomaterial Model of Glioblastoma.

Similar Datasets

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