Erlotinib resistance in EGFR-amplified glioblastoma cells is associated with upregulation of EGFRvIII and PI3Kp110δ
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Erlotinib resistance in EGFR-amplified glioblastoma cells is associated with upregulation of EGFRvIII and PI3Kp110δ. / Schulte, Alexander; Liffers, Katrin; Kathagen, Annegret; Riethdorf, Sabine; Zapf, Svenja; Merlo, Adrian; Kolbe, Katharina; Westphal, Manfred; Lamszus, Katrin.
In: NEURO-ONCOLOGY, Vol. 15, No. 10, 01.10.2013, p. 1289-301.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Erlotinib resistance in EGFR-amplified glioblastoma cells is associated with upregulation of EGFRvIII and PI3Kp110δ
AU - Schulte, Alexander
AU - Liffers, Katrin
AU - Kathagen, Annegret
AU - Riethdorf, Sabine
AU - Zapf, Svenja
AU - Merlo, Adrian
AU - Kolbe, Katharina
AU - Westphal, Manfred
AU - Lamszus, Katrin
PY - 2013/10/1
Y1 - 2013/10/1
N2 - BACKGROUND: The 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.METHODS: Functional 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.RESULTS: Erlotinib 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.CONCLUSIONS: EGFRvIII 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.
AB - BACKGROUND: The 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.METHODS: Functional 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.RESULTS: Erlotinib 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.CONCLUSIONS: EGFRvIII 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.
KW - Animals
KW - Apoptosis
KW - Blotting, Western
KW - Brain Neoplasms
KW - Cell Survival
KW - Drug Resistance, Neoplasm
KW - Flow Cytometry
KW - Fluorescent Antibody Technique
KW - Forkhead Transcription Factors
KW - Gene Amplification
KW - Glioblastoma
KW - Humans
KW - Immunoenzyme Techniques
KW - In Situ Hybridization, Fluorescence
KW - Mice
KW - Mice, Nude
KW - Phosphatidylinositol 3-Kinases
KW - Protein Kinase Inhibitors
KW - Quinazolines
KW - Receptor, Epidermal Growth Factor
KW - Signal Transduction
KW - Tumor Cells, Cultured
U2 - 10.1093/neuonc/not093
DO - 10.1093/neuonc/not093
M3 - SCORING: Journal article
C2 - 23877316
VL - 15
SP - 1289
EP - 1301
JO - NEURO-ONCOLOGY
JF - NEURO-ONCOLOGY
SN - 1522-8517
IS - 10
ER -
