Biomarkers to Predict Response to Epidermal Growth Factor Receptor Inhibitors

Haas‐Kogan, Daphne A.; Prados, Michael D.; Lamborn, Kathleen R.; Tihan, Tarık; Berger, Mitchel S.; Stokoe, David

doi:10.4161/cc.4.10.2105

Cited by 69 publications

(32 citation statements)

References 39 publications

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“…Nevertheless, our experiments concur to the demonstration that therapeutic concentrations of gefitinib are high, as-despite our use of an in vitro model-the concentration needed to obtain full anti-invasive and antiproliferative effects in responding tumors was in the 10 μmol/L range. It can be argued that EGFR amplification (47) and EGFRvIII expression (27) are in the same time molecular determinants of response and, paradoxically, factors of relative resistance to treatment. Indeed, gene amplification of the target has been associated with acquired resistance to imatinib mesylate (STI571, Gleevec) in chronic myelogenous leukemia (48) and EGFRvIII expression was experimentally associated to a relative resistance to gefitinib in glioblastoma multiforme (49).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma

Guillamo

Boüard

Valable³

et al. 2009

Clinical Cancer Research

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Purpose: Epidermal growth factor receptor (EGFR) signal transduction pathways are implicated in malignant glioma aggressiveness and promote tumor cell invasion, proliferation, and angiogenesis. Nevertheless, response to EGFR tyrosine kinase inhibitor gefitinib (Iressa, ZD1839) has been disappointing in clinical trials. One potential explanation may come from the diversity of molecular alterations seen in gliomas. To validate that hypothesis, we have investigated responses to gefitinib on various tumor parameters in human malignant gliomas that exhibited different molecular alterations. Experimental Design: We used a panel of six human malignant gliomas from established xenografts characterized for their genetic (EGFR, PTEN, TP53, and CDKN2A) and molecular (EGFR, PTEN, ERK, and Akt) alterations. Tumors were treated with gefitinib (1 or 10 μmol/L) for prolonged periods (8 or 16 days) in an organotypic brain slice model that allowed quantification of invasion, proliferation, and angiogenesis. Results: In nontreated tumors, EGFR amplification was associated with profuse tumor cell invasion. After treatment, invasion was inhibited in tumors with EGFR amplification in a dose-dependent manner. Treatment had only antiproliferative effect in two of three tumors with EGFR amplification. Tumors with PTEN loss were resistant to treatment. We did not observe shrinkage of the tumors after treatment. None of the tumors had mutations of the EGFR kinase domain. Gefitinib had similar antiangiogenic effect in all of the tumors. Conclusions: Gefitinib reduces cell invasion in EGFR amplified tumors. PTEN loss of expression seems to be a determinant of resistance. Interestingly, inhibition of angiogenesis by gefitinib seems independent on the EGFR genetic status of the tumors.Glioblastoma multiforme is the most frequent and aggressive primary brain tumor (1). Despite vigorous therapies combining surgical resection, radiotherapy, and chemotherapy, this tumor rapidly recurs, often causing patient death within 2 years after initial diagnosis (2). Resistance to conventional anticancer therapies is, in part, due to the invasion of tumor cells into the brain parenchyma and the high degree of angiogenesis associated with glioblastoma multiforme (3, 4). Attempts to understand aggressiveness of malignant gliomas have focused on genetic and molecular alterations of tumor cells. Epidermal growth factor receptor (EGFR) gene amplification is one of the most frequent alteration, occurring in 30% to 40% of glioblastoma multiforme (5, 6). Genomic amplification is often associated with mutations of the receptor, usually a deletion of exons 2 to 7, usually give rise to a truncated constitutively activated receptor called EGFRvIII (7,8). EGFR gene codes for a transmembrane receptor tyrosine kinase that mediates cellular signaling pathways involved in cell survival, cell cycle progression, angiogenesis, and tumor cell invasion (9,10 receptor activates intracellular signaling cascades, including the mitotic ras/mitogen-activated protein kinase a...

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma

Guillamo

Boüard

Valable³

et al. 2009

Clinical Cancer Research

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“…3). In early clinical trials, 10% to 20% of malignant glioma patients seem to derive benefit from the EGFR kinase inhibitors erlotinib and gefitinib (4,5). We have recently shown that coexpression of the EGFRvIII oncogene and the PTEN tumor suppressor protein is strongly associated with clinical response to EGFR kinase inhibitor therapy in two independent sets of malignant glioma patients (6).…”

Section: Introductionmentioning

confidence: 99%

Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells

Wang¹,

Lu²,

Zhu³

et al. 2006

Cancer Research

222

166

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The epidermal growth factor receptor (EGFR) is commonly amplified, overexpressed, and mutated in glioblastoma, making it a compelling molecular target for therapy. We have recently shown that coexpression of EGFRvIII and PTEN protein by glioblastoma cells is strongly associated with clinical response to EGFR kinase inhibitor therapy. PTEN loss, by dissociating inhibition of the EGFR from downstream phosphatidylinositol 3-kinase (PI3K) pathway inhibition, seems to act as a resistance factor. Because 40% to 50% of glioblastomas are PTEN deficient, a critical challenge is to identify strategies that promote responsiveness to EGFR kinase inhibitors in patients whose tumors lack PTEN. Here, we show that the mammalian target of rapamycin (mTOR) inhibitor rapamycin enhances the sensitivity of PTENdeficient tumor cells to the EGFR kinase inhibitor erlotinib. In two isogenic model systems (U87MG glioblastoma cells expressing EGFR, EGFRvIII, and PTEN in relevant combinations, and SF295 glioblastoma cells in which PTEN protein expression has been stably restored), we show that combined EGFR/mTOR kinase inhibition inhibits tumor cell growth and has an additive effect on inhibiting downstream PI3K pathway signaling. We also show that combination therapy provides added benefit in promoting cell death in PTEN-deficient tumor cells. These studies provide strong rationale for combined mTOR/EGFR kinase inhibitor therapy in glioblastoma patients, particularly those with PTEN-deficient tumors.

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“…13,14 The epidermal growth factor (EGF) receptor (EGFR) pathway is a clear example of a signal transduction pathway that has been associated with development, progression, and resistance to treatment with cytotoxic drugs of a number of human solid tumors including breast. [17][18][19][20][21][22][23][24][25][26] EGFR is part of the tyrosine kinase receptor family that also includes erbB2, erbB3, and erbB4. 20 EGFR are large proteins, which reside in the cell membrane and with the exception of erbB2 each has a specific extracellular ligand-binding domain, a transmembrane and intracellular domain, which has tyrosine kinase activity.…”

Section: Introductionmentioning

confidence: 99%

EGF Induces Cell Motility and Multi-Drug Resistance Gene Expression in Breast Cancer Cells

García¹,

Franklin²,

McCubrey³

2006

Cell Cycle

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The epidermal growth factor receptor (EGFR) is important for normal development, differentiation, and cell proliferation. Deregulation of EGFR has been observed in breast cancer. EGFR and signal pathways activated by these receptors have been associated with an advanced tumor stage and a poor clinical prognosis in breast cancer; however, the precise mechanisms responsible for this process are still not known. Here we show that treatment of MCF-7 breast cancer cells with EGF activated Akt and ERK, induced morphological changes, and increased cell motility. In addition, the constitutive expression of Raf-1 and the use of a MEK inhibitor demonstrated the participation of the Raf/MEK/ERK pathway in these processes. Importantly we detected that EGF induced MRP-1, 3, 5 and 7 gene expression and an increase in MRP1 promoter activity. In conclusion, treatment of MCF-7 breast cancer cells with EGF, in the absence of other growth factors, resulted in activation of EGFR signal transduction pathways; which were related with cell motility and drug resistance.

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Biomarkers to Predict Response to Epidermal Growth Factor Receptor Inhibitors

Cited by 69 publications

References 39 publications

Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma

Molecular Mechanisms Underlying Effects of Epidermal Growth Factor Receptor Inhibition on Invasion, Proliferation, and Angiogenesis in Experimental Glioma

Mammalian Target of Rapamycin Inhibition Promotes Response to Epidermal Growth Factor Receptor Kinase Inhibitors in PTEN-Deficient and PTEN-Intact Glioblastoma Cells

EGF Induces Cell Motility and Multi-Drug Resistance Gene Expression in Breast Cancer Cells

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