Molecular Determinants of the Response of Glioblastomas to EGFR Kinase Inhibitors

Mellinghoff, Ingo K.; Wang, Maria Y.; Vivanco, Igor; Haas‐Kogan, Daphne A.; Zhu, Shaojun; Dia, Ederlyn Q.; Lu, Kan V.; Yoshimoto, Koji; Huang, Julie H.; Chute, Dennis J.; Riggs, Bridget L.; Horvath, Steve; Liau, Linda M.; Cavenee, Webster K.; Rao, P. Nagesh; Beroukhim, Rameen; Peck, Timothy C.; Lee, Jeffrey C.; Sellers, William R.; Stokoe, David; Prados, Michael D.; Cloughesy, Timothy F.; Sawyers, Charles L.; Mischel, Paul S.

doi:10.1056/nejmoa051918

Cited by 1,331 publications

(1,043 citation statements)

References 38 publications

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“…Among patients with recurrent malignant glioma, response to EGFR inhibitors was observed in a subset of patients despite the lack of mutations in the EGFR kinase domain, and such a response was correlated with loss of PTEN and expression of EGFR class III variant (EGFRvIII), a mutant form of EGFR that lacks 267 amino acids from its extracellular domain. 46,47 In conclusion, expression of EGFR and/or ErbB-2 can be detected in a sizeable subset of rhabdomyosarcoma tumors, with no evidence of amplification at 7p11.2 and 17q12 or mutations in the EGFR tyrosine kinase domain. Notably, EGFR expression correlates with the embryonal subtype independent of other variables such as stage, age, and gender, and it is also more likely to coexpress EGFR and ErbB-2.…”

Section: Discussionmentioning

confidence: 78%

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

et al. 2006

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Both epidermal growth factor receptor (EGFR) and ErbB-2 play an important role in cancer biology and constitute promising molecular targets of therapy. EGFR and ErbB-2 expression has been observed in rhabdomyosarcoma cell lines but not analyzed systematically in rhabdomyosarcoma tumors. Tissue microarray sections representing 66 rhabdomyosarcoma tumors (34 embryonal rhabdomyosarcoma, 32 alveolar rhabdomyosarcoma) were surveyed by immunohistochemistry using antibodies specific for EGFR and ErbB-2. Immunostains were assessed for intensity (0: no immunostaining; 1: weak; 2: moderate; 3: strong) and percentage of at least 500 neoplastic cells exhibiting membranous or membranous and cytoplasmic immunostaining. EGFR and ErbB-2 expression was considered positive if the product of intensity and percentage was greater than 10. Patients had a median age of 5.7 years (range 8 months-19.1 years), and of 65/ 66 patients, 38 were males and 27 were females. Expression of ErbB-2 was identified in 22/66 (33%) cases and tended to be more frequent in the alveolar subtype (13/32, 41%, vs 9/34, 26%, P ¼ 0.30). Expression of EGFR was identified in 31/66 (47%) cases and correlated with the embryonal subtype (26/34, 76%, vs 5/32, 16%, Po0.0001) independent of stage, age, and gender. Coexpression of EGFR and ErbB-2 was identified in eight tumors, of which six were embryonal rhabdomyosarcoma. None of the cases exhibited EGFR or ErbB-2 gene amplification, as assessed using fluorescence in situ hybridization. Furthermore, analysis of 11 additional rhabdomyosarcoma tumors (six alveolar; five embryonal) revealed no evidence of mutations in EGFR exons 18, 19, 20, and 21. In summary, expression of EGFR and/or ErbB-2 is detected in a sizeable subset of rhabdomyosarcoma tumors without evidence of EGFR or ErbB-2 amplification or mutations in the EGFR tyrosine kinase domain. Notably, expression of EGFR correlates with the embryonal subtype, which is also more likely to coexpress EGFR and ErbB-2.

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Section: Discussionmentioning

confidence: 78%

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

et al. 2006

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“…[92][93][94] EGFRvIII activates the phosphatidylinositol 3 0 kinase (PIK3CA) signaling pathway, which provides critical information for cell survival, proliferation, and motility. 95,96 The true incidence and clinical significance of EGFRvIII mutations are not yet clearly defined. There have also been reports that EGFRvIII mutation in lung cancer correlates with increased EGFR copy number.…”

Section: Egfrviii Mutationmentioning

confidence: 99%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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“…The expression of the EGFRvIII in glioblastoma multiforme is a negative prognostic indicator (Shinojima et al, 2003;Heimberger et al, 2005). However, it has been reported recently that the co-expression of the EGFRvIII and the tumor-suppressor protein PTEN predicts response of patients with glioblastoma to the EGFR TK inhibitors (Mellinghoff et al, 2005). In addition, the expression of the EGFRvIII has been reported in breast, non-smallcell lung, ovarian, and prostate carcinomas, but not in normal tissues (Garcia de Palazzo et al, 1993;Moscatello et al, 1995;Wikstrand et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

et al. 2006

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The overexpression or mutation of tyrosine kinases (TKs), such as the epidermal growth factor receptor (EGFR), can lead to the development of cancer. The most common mutation of the EGFR in glioblastomas is the deletion of exons 2-7 known as the EGFRvIII. This mutant receptor cannot bind EGF but, instead, is constitutively active. The Cbl family of ubiquitin ligases (Cbl, Cbl-b, and Cbl-c) targets the activated EGFR for degradation. As the EGFRvIII is transforming, we investigated whether it could be downregulated by the Cbl proteins. The over-expression of all three Cbl proteins resulted in the ubiquitination and degradation of the EGFRvIII. As with the wild-type EGFR, the TK-binding domain and the RING finger of Cbl-b are sufficient for the downregulation of the EGFRvIII. Also, we found that Cbl-b is recruited to the EGFRvIII and inhibits the transformation of NIH 3T3 cells by the EGFRvIII. Mutation of the Cbl-binding site (Y1045F) in the EGFRvIII inhibits its ubiquitination and downregulation by Cbl-b and enhances its ability to transform. Furthermore, the EGFR TK inhibitor, AG 1478, prevents the downregulation of the EGFRvIII by the Cbl proteins and antagonizes the ability of an immunotoxin directed against the EGFRvIII to kill cells expressing this receptor. In conclusion, the EGFR-vIII does not transform by escaping regulation by Cbl proteins and this activation-induced downregulation of the EGFRvIII has an important role in mediating the toxicity of anti-EGFRvIII immunotoxins.

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Molecular Determinants of the Response of Glioblastomas to EGFR Kinase Inhibitors

Abstract: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.

Cited by 1,331 publications

References 38 publications

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma

Molecular pathology of lung cancer: key to personalized medicine

EGFRvIII undergoes activation-dependent downregulation mediated by the Cbl proteins

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