Antitumor effect in medulloblastoma cells by gefitinib: Ectopic HER2 overexpression enhances gefitinib effects in vivo

Daniela Meco, Tiziana Servidei, Anna Riccardi, Cristiano Ferlini, Gabriella Cusano, Gian Franco Zannoni, Felice Giangaspero, Riccardo Riccardi

Research output: Contribution to journalArticlepeer-review

Abstract

The effects of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on cell growth and signaling were evaluated in three medulloblastoma (MB) cell lines (D283, D341, Daoy), one supratentorial primitive neuroectodermal tumor cell line (PFSK), and four MB primary cultures. Cell lines showed diverse expression of EGFR and human epidermal receptor 2 (HER2), with high levels of constitutively activated HER2 in the HER2-overexpressing D341 and D283 cells. Gefi-tinib sensitivity varied across lines and was not related to expression of HER receptors or receptor baseline activation. Gefitinib induced G 0/G 1 arrest in all lines, whereas apoptosis was dose-dependently induced only in D283 and D341 cells. The molecular response to gefi-tinib was investigated in Daoy and D341 lines, which showed a higher (half-maximal inhibitory concentration [IC 50], 3.8 μM) and lower (IC 50, 6.6 μM) sensitivity to the agent, respectively. Gefitinib inhibited constitutive and EGF-triggered EGFR phosphorylation in both lines but was ineffective in constitutive activation of HER2 in D341 cells. Phosphorylated AKT inhibition paralleled that of phosphorylated EGFR, suggesting the presence of an autocrine gefitinib-sensitive EGFR/AKT pathway. On the whole, EGF-dependent signaling was less responsive to ligand stimulation and gefitinib inhibition in D341 cells, which correlated with the lower sensitivity to gefitinib's antiproliferative effect of this line. In vivo, the growth of D341 and Daoy xenografts treated with gefitinib at 150 mg/kg per day was inhibited by approximately 50%. Ectopically overexpressed HER2 in Daoy cells significantly increased sensitivity to gefitinib's antitumor effects in vivo (tumor volume inhibition = 78%). Our data indicate that gefitinib might be a molecularly targeted agent for the treatment of MB.

Original languageEnglish
Pages (from-to)250-259
Number of pages10
JournalNeuro-Oncology
Volume11
Issue number3
DOIs
Publication statusPublished - Jun 2009

Keywords

  • EGFR
  • Gefitinib
  • HER2
  • In vivo
  • Medulloblastoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Fingerprint

Dive into the research topics of 'Antitumor effect in medulloblastoma cells by gefitinib: Ectopic HER2 overexpression enhances gefitinib effects in vivo'. Together they form a unique fingerprint.

Cite this