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

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]

Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib

“…In the present study, we found no correlation between the erlotinib-related cellular phenotype and the expression of certain genes (EGFR, PTEN, and AKT1) 5,13,19,23 implicated in modulating GBM cells' response to erlotinib, or proposed to participate in GBM pathogenesis. 11,18,22,27 Although determination of protein phosphorylation was not our goal in the present study, a putative role for these gene products in the response of GBM cells to erlotinib was not evident at the level of gene expression.…”

Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240

“…Finally, on the basis of our findings that FGF signaling can drive phosphorylation of PTEN, we tested the potential for FGF to mediate resistance to EGFR inhibition. Consistent with the observed sensitivity of GBM39 to erlotinib in vivo (34), in the absence of exogenous growth factors treatment of GBM39 cells with erlotinib for 48 h resulted in cell rounding and detachment from the laminin substrate, induction of poly (ADP-ribose) polymerase (PARP) cleavage and loss of viability as measured by WST1 assay, all of which were blocked by the inclusion of bFGF in the medium (Fig. 5 B and C and SI Appendix, Fig.…”

Pathway Analysis of Glioblastoma Tissue after Preoperative Treatment with the EGFR Tyrosine Kinase Inhibitor Gefitinib—A Phase II Trial

“…15) and human glioblastoma xenograft models (16) to allow future patient selection. Several sets of markers with predictive value for response to TKIs were proposed, comprising expression of EGFR, amplification of the EGFR gene, lack of elevated levels of AKT phosphorylation, and absence of EGFRvIII expression (17), whereas another study suggested better response of tumors with expression of EGFRvIII and expression of PTEN (18).…”