Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. Export

@article{citeulike:882382, abstract = {BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.}, address = {Department of Molecular and Medical Pharmacology and Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles 90095-1732, USA.}, author = {Mellinghoff, I. K. and Wang, M. Y. and Vivanco, I. and Haas-Kogan, D. A. and Zhu, S. and Dia, E. Q. and Lu, K. V. and Yoshimoto, K. and Huang, J. H. and Chute, D. J. and Riggs, B. L. and Horvath, S. and Liau, L. M. and Cavenee, W. K. and Rao, P. N. and Beroukhim, R. and Peck, T. C. and Lee, J. C. and Sellers, W. R. and Stokoe, D. and Prados, M. and Cloughesy, T. F. and Sawyers, C. L. and Mischel, P. S.}, citeulike-article-id = {882382}, citeulike-linkout-0 = {http://dx.doi.org/10.1056/NEJMoa051918}, citeulike-linkout-1 = {http://content.nejm.org/cgi/content/abstract/353/19/2012?ijkey=f50128e267fd310199f83046c8e9a2da231f9a17&keytype2=tf_ipsecsha}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16282176}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16282176}, day = {10}, doi = {10.1056/NEJMoa051918}, issn = {1533-4406}, journal = {N Engl J Med}, keywords = {amplification, drug, egfr, mutation, pten, sensitivity}, month = {November}, number = {19}, pages = {2012--2024}, posted-at = {2006-10-03 07:19:19}, priority = {2}, title = {Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors.}, url = {http://dx.doi.org/10.1056/NEJMoa051918}, volume = {353}, year = {2005} }

TY - JOUR ID - citeulike:882382 L3 - citeulike-article-id:882382 N2 - BACKGROUND: The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. METHODS: We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. RESULTS: Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. CONCLUSIONS: Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors. IS - 19 JF - N Engl J Med SN - 1533-4406 AD - Department of Molecular and Medical Pharmacology and Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles 90095-1732, USA. EP - 2024 TI - Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. VL - 353 SP - 2012 KW - amplification KW - drug KW - egfr KW - mutation KW - pten KW - sensitivity AU - Mellinghoff, IK AU - Wang, MY AU - Vivanco, I AU - Haas-Kogan, DA AU - Zhu, S AU - Dia, EQ AU - Lu, KV AU - Yoshimoto, K AU - Huang, JH AU - Chute, DJ AU - Riggs, BL AU - Horvath, S AU - Liau, LM AU - Cavenee, WK AU - Rao, PN AU - Beroukhim, R AU - Peck, TC AU - Lee, JC AU - Sellers, WR AU - Stokoe, D AU - Prados, M AU - Cloughesy, TF AU - Sawyers, CL AU - Mischel, PS PY - 2005/11/10/ UR - http://dx.doi.org/10.1056/NEJMoa051918 ER -