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Research Articles: Therapeutics, Targets, and Development

Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel

¹ Department of Radiation Oncology, ² Division of Medical Oncology, ³ Department of Laboratory Medicine and Pathology, ⁴ Division of Biostatistics, and ⁵ Neuroscience Graduate Program, Mayo Clinic, Rochester, Minnesota; and ⁶ Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, California

Requests for reprints: C. David James, Department of Neurological Surgery, University of California, San Francisco, Room HSW 792, 513 Parnassus Avenue, San Francisco, CA 94143. Phone: 415-476-5876. E-mail: david.james{at}ucsf.edu

Abstract

In the current study, we examined a panel of serially passaged glioblastoma xenografts, in the context of an intracranial tumor therapy response model, to identify associations between glioblastoma molecular characteristics and tumor sensitivity to the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib. From an initial evaluation of 11 distinct glioblastoma xenografts, two erlotinib-sensitive tumors were identified, each having amplified EGFR and expressing wild-type PTEN. One of these tumors expressed truncated EGFRvIII, whereas the other expressed full-length EGFR. Subsequent cDNA sequence analysis revealed the latter tumor as expressing an EGFR sequence variant with arginine, rather than leucine, at amino acid position 62; this was the only EGFR sequence variant identified among the 11 xenografts, other than the aforementioned vIII sequence variant. EGFR cDNAs were then examined from 12 more xenografts to determine whether additional missense sequence alterations were evident, and this analysis revealed one such case, expressing threonine, rather than alanine, at amino acid position 289 of the extracellular domain. This glioblastoma was also amplified for EGFR, but did not display significant erlotinib sensitivity, presumably due to its lacking PTEN expression. In total, our study identified two erlotinib-sensitive glioblastoma xenografts, with the common molecular characteristics shared by each being the expression of wild-type PTEN in combination with the expression of amplified and aberrant EGFR. [Mol Cancer Ther 2007;6(3):1167–74]

Grant support: NIH NS49720 (C.D. James), CA097257 (C.D. James), CA108961 (J.N. Sarkaria, E. Galanis, and C. Giannini), CA25224 (J.N. Sarkaria, E. Galanis, and C. Giannini), and CA114740 (J.N. Sarkaria, E. Galanis, and C. Giannini); American Cancer Society Research Scholar Grant (J.N. Sarkaria); and Accelerate Brain Cancer Cure (J.N. Sarkaria and C.D. James).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/ 9/06; revised 12/20/06; accepted 1/30/07.

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