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Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors.

ABSTRACT: Because a subpopulation of cancer stem cells (tumor-initiating cells, TICs) is believed to be responsible for the development, progression, and recurrence of many tumors, we evaluated the in vitro sensitivity of human glioma TICs to epidermal growth factor receptor (EGFR) kinase inhibitors (erlotinib and gefitinib) and possible molecular determinants for their effects. Cells isolated from seven glioblastomas (GBM 1-7) and grown using neural stem cell permissive conditions were characterized for in vivo tumorigenicity, expression of tumor stem cell markers (CD133, nestin), and multilineage differentiation properties, confirming that these cultures are enriched in TICs. TIC cultures were challenged with increasing concentrations of erlotinib and gefitinib, and their survival was evaluated after 1-4 days. In most cases, a time- and concentration-dependent cell death was observed, although GBM 2 was completely insensitive to both drugs, and GBM 7 was responsive only to the highest concentrations tested. Using a radioligand binding assay, we show that all GBM TICs express EGFR. Erlotinib and gefitinib inhibited EGFR and ERK1/2 phosphorylation/activation in all GBMs, irrespective of the antiproliferative response observed. However, under basal conditions GBM 2 showed a high Akt phosphorylation that was completely insensitive to both drugs, whereas GBM 7 was completely insensitive to gefitinib, and Akt inactivation occurred only for the highest erlotinib concentration tested, showing a precise relationship with the antiproliferative effects of the drug. Interestingly, in GBM 2, phosphatase and tensin homolog expression was significantly down-regulated, possibly accounting for the insensitivity to the drugs. In conclusion, glioma TICs are responsive to anti-EGFR drugs, but phosphatase and tensin homolog expression and Akt inhibition seem to be necessary for such effect.

SUBMITTER: Griffero F

PROVIDER: S-EPMC2652334 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors.

Griffero Fabrizio F Daga Antonio A Marubbi Daniela D Capra Maria Cristina MC Melotti Alice A Pattarozzi Alessandra A Gatti Monica M Bajetto Adriana A Porcile Carola C Barbieri Federica F Favoni Roberto E RE Lo Casto Michele M Zona Gianluigi G Spaziante Renato R Florio Tullio T Corte Giorgio G

The Journal of biological chemistry 20090114 11

Because a subpopulation of cancer stem cells (tumor-initiating cells, TICs) is believed to be responsible for the development, progression, and recurrence of many tumors, we evaluated the in vitro sensitivity of human glioma TICs to epidermal growth factor receptor (EGFR) kinase inhibitors (erlotinib and gefitinib) and possible molecular determinants for their effects. Cells isolated from seven glioblastomas (GBM 1-7) and grown using neural stem cell permissive conditions were characterized for ...[more]

PMID: 19147502

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Project description:Background: Choroidal metastases are the most common eye metastatic site. The prevalence of choroidal metastases in NSCLC patients has been reported to vary from 0.2 to 7% in historical series. Although previously reported, little is known about choroidal metastasis in Epidermal Growth Factor Receptor (EGFR)-mutant Non-small cell lung cancer (NSCLC). This study sought to describe the prevalence of choroidal metastases among patients with EGFR-mutated NSCLC and their characteristics, and to estimate their impact on prognosis.Methods: We conducted a single-center retrospective study including all consecutive metastatic EGFR-mutant NSCLC patients, from Sept. 2015 to Oct. 2018. The EGFR-mutant NSCLC patients were identified via the Department of Genetics' files. Patients who exhibited choroidal metastases were compared to patients without choroidal metastases. Kaplan-Meier analysis and log-rank test were conducted to assess median overall survival (OS) from diagnosis for the two groups. The study was approved by the IRB as CEPRO number #2020-010.Results: Prevalence of choroidal metastases in EGFR-mutated NSCLCs was 8.4% (7/83). Five were women, and four current or former smokers. Molecular analysis showed three tumors with exon 19 deletion, three with L858R mutation, and one with complex exon 21 mutation. The choroidal metastases were symptomatic in six/seven patients. Visual disturbances decreased in all but one symptomatic cases upon EGFR TKI, and the choroidal response was maintained over time. Median follow-up was 42.2 mo (95%CI [37.2-47.1]). Median OS in the choroidal metastasis group was 23.4 mo (95%CI [0.1-51.4]) versus 27.9 mo (95%CI [16.9-38.9]) in the non-choroidal metastasis group (p?=?0.32). In the choroidal metastasis group, 2-year and 5-year OS were 47.6 and 0%, respectively, versus 55.8 and 26.3% in the non-choroidal metastasis subset.Conclusions: Choroidal metastases in NSCLC EGFR-mutant patients are rare but should be systematically suspected in case of visual disturbance. TKIs are efficient for treating visual symptoms. Whether choroidal metastases confer a worse prognosis remains unclear owing to the third-generation EGFR TKI osimertinib first-line registration.

Dataset Information

Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors.

Publications

Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors.

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