Structural alterations of the epidermal growth factor receptor gene in human gliomas.

Wong, Albert J.; Ruppert, J. Michael; Bigner, Sandra H.; Grzeschik, Carl H.; Humphrey, Peter A.; Bigner, Darrell S.; Vogelstein, Bert

doi:10.1073/pnas.89.7.2965

Cited by 757 publications

(520 citation statements)

References 23 publications

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“…19 --21 A common example of abnormal RTK activation is the epidermal growth factor receptor class III variant, which is present in a substantial proportion of malignant gliomas and other human cancers, but completely absent in normal tissues. 22,23 This variant results from a transcript having an 801-bp in-frame deletion of EGFR that corresponds to exons 2 --7, which leads to the generation of a protein with a truncated extracellular domain. 21,24 Several molecular mechanisms have been implicated in the oncogenic pathway with epidermal growth factor receptor class III variant downstream signaling.…”

Section: Discussionmentioning

confidence: 99%

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

et al. 2012

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Anaplastic lymphoma kinase (ALK) was originally identified from a rare subtype of non-Hodgkin's lymphomas carrying t(2;5)(p23;q35) translocation, where ALK was constitutively activated as a result of a fusion with nucleophosmin (NPM). Aberrant ALK fusion proteins were also generated in inflammatory fibrosarcoma and a subset of non-small-cell lung cancers, and these proteins are implicated in their pathogenesis. Recently, ALK has been demonstrated to be constitutively activated by gene mutations and/or amplifications in sporadic as well as familial cases of neuroblastoma. Here we describe another mechanism of aberrant ALK activation observed in a neuroblastoma-derived cell line (NB-1), in which a short-form ALK protein (ALK del2-3 ) having a truncated extracellular domain is overexpressed because of amplification of an abnormal ALK gene that lacks exons 2 and 3. ALK del2-3 was autophosphorylated in NB-1 cells as well as in ALK del2-3 -transduced cells and exhibited enhanced in vitro kinase activity compared with the wild-type kinase. ALK del2-3 -transduced NIH3T3 cells exhibited increased colony-forming capacity in soft agar and tumorigenicity in nude mice. RNAi-mediated ALK knockdown resulted in the growth suppression of ALK del2-3 -expressing cells, arguing for the oncogenic role of this mutant. Our findings provide a novel insight into the mechanism of deregulation of the ALK kinase and its roles in neuroblastoma pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

et al. 2012

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“…The overexpression of EGFR has been observed in both premalignant lesions and malignant tumors of the lung, and occurs in 40-80% of patients with NSCLC (Salomon et al, 1995;Grandis and Sok, 2004;Merrick et al, 2006). EGFR overexpression was suggested to result primarily from epigenetic causes, including transcriptional activation; however, gene amplification and oncogenic viruses can also have an important function (Wong et al, 1992;Rubin Grandis et al, 1996a, b;Grandis and Sok, 2004). In tumors, the EGFR signaling network can result in the activation of MAPK, PLCg, PI3K/AKT, the STAT transcription factors, proto-oncogene transcription factors, such as fos, jun and myc, and zinc-finger-containing transcription factors, such as Sp1 and Egr1 (Grandis and Sok, 2004).…”

Section: Egfr and Her2 Overexpressionmentioning

confidence: 99%

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

2009

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Epidermal growth factor receptor (EGFR) and HER2 are cell surface receptor tyrosine kinases (TKs) that transduce growth signals through dimerization with HER family receptors. The heterodimerization of EGFR with HER2 induces a more potent activation of EGFR TK than does EGFR homodimerization. When tumor cells overexpress both EGFR and HER2, they exhibit aggressive tumor cell growth, owing to the increased potential for EGFR/HER2 heterodimerization and signaling. Gefitinib and erlotinib are EGFR TK inhibitors (EGFR TKIs) and have antitumor activity in 8-18% of patients with advanced non-small-cell lung cancer (NSCLC). Certain patient subsets are particularly responsive to EGFR TKIs. Analyses of biomarkers from patients in clinical studies of EGFR TKIs show correlations between objective tumor response and EGFR overexpression, as detected by immunohistochemistry and increased gene copy number measured by fluorescence in situ hybridization analysis. Furthermore, NSCLC tumors that overexpress both EGFR and HER2 are more sensitive to EGFR TKIs than are tumors that overexpress EGFR but are HER2 negative. Therefore, the measurement of EGFR and HER2 protein expression and the gene copy number in NSCLC tumors may have a prognostic value in NSCLC and a predictive value for identifying patients likely to benefit from an EGFR TKI. These considerations suggest that the simultaneous inhibition of EGFR and HER2 may warrant further study in patients with NSCLC.

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“…Oncogenic Ras mutations have not been discovered in human astrocytomas (Bos, 1989;Tuzi et al, 1991), which constitute the most common primary malignancy involving the central nervous system (Zimmerman, 1969). However, it has been demonstrated that high grade (grade IV) astrocytomas, known as glioblastoma multiforme (GBM), express high levels of ligand-dependent and -independent growth factor receptors (Fleming et al, 1992;Guha et al, 1995a;Libermann et al, 1984;NisteÂ r et al, 1988;Steck et al, 1988;Sugawa et al, 1990;Wong et al, 1992) which are functionally relevant for tumour growth (Guha et al, 1995a,b;Shamah et al, 1993). We have demonstrated these various receptors to result in a functional activation of the Ras pathway in a wide range of astrocytoma cell lines (U87, U118, U138, U343 and U373-MG cells).…”

Section: Introductionmentioning

confidence: 99%

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

1999

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While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras.GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their e ect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its e ect. L-744,832 demonstrates both cytostatic and cytotoxic e ects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in highgrade astrocytomas (EGFRvIII/p140 EGF-R ) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchoragedependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G 1 /M and G 2 /S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21 WAF1/CIP1 , but this induction is not necessary for the cell cycle inhibitory e ects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic e ects.

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Structural alterations of the epidermal growth factor receptor gene in human gliomas.

Cited by 757 publications

References 23 publications

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

Aberrant activation of ALK kinase by a novel truncated form ALK protein in neuroblastoma

Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

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