Epidermal Growth Factor Receptor as a Genetic Therapy Target for Carcinoma Cell Radiosensitization

Abstract

Transduction of MDA-MB-231 xenograft tumors with Ad-EGFR-CD533 conferred a dominant-negative EGFR phenotype and induced tumor radiosensitization. Therefore, disruption of EGFR function through overexpression of EGFR-CD533 may hold promise as a gene therapeutic approach to enhance the sensitivity of tumor cells to ionizing radiation.

Inhibition of the Type III Epidermal Growth Factor Receptor Variant Mutant Receptor by Dominant-Negative EGFR-CD533 Enhances Malignant Glioma Cell Radiosensitivity

“…We have demonstrated previously (19) that ionizing radiation induced an immediate activation of EGFRwt in xenograft tumors, which showed a maximum activation within 10 minutes after a single 4-Gy radiation exposure. Thus, we investigated further the effects of ionizing radiation on EGFRvIII tyrosine phosphorylation in vivo.…”

“…Our previous studies (19) have shown that expression of EGFR-CD533 reduced the basal and radiation-stimulated tyrosine phosphorylation of EGFRwt. In the present study, we examined whether expression of EGFR-CD533 could also modulate EGFRvIII activity.…”

“…We have shown that a genetic approach of overexpressing EGFR-CD533, a dominant-negative (DN) variant of EGFR lacking 533 amino acids of the cytoplasmic domain (15,16), disrupts this cytoprotective signaling by EGFRwt and its downstream effectors (17,18). Furthermore, expression of EGFR-CD533 inhibits basal and radiation-induced EGFR activation and radiosensitizes both in vitro and in vivo (19). An important next step in the mechanistic analyses is to investigate whether expression of EGFR-CD533 also modulates EGFRvIII activity because EGFRvIII is commonly expressed in tumors, and previous findings suggest the inability of EGFRvIII to interact with other ERBB receptors (3,8).…”

EGFRvIII-mediated radioresistance through a strong cytoprotective response

“…This difference changed to a 2.5-fold increase in relative radioresistance of EGFRvIII expressing cells after 4 Gy. These data represent the most direct demonstration that radiation-induced activation of EGFR species provides a strong cytoprotective signal with increased radioresistance through enhanced proliferation and repair Reardon et al, 1999;Lammering et al, 2001a). From studies on p185neu (ERBB2), the impact of ERBB receptors on cellular radiosensitivity may not be limited to EGFR and its mutants (O'Rourke et al, 1997(O'Rourke et al, , 1998a, but likely depend upon the entire ERBB expression profile of a given tumor cell (Bowers et al, 2001;Lammering et al, 2001a;Contessa et al, 2002).…”

“…To date, mechanistic studies on this naturally occurring truncated receptor have been limited since its spontaneous expression is only seen in vivo in naturally occurring tumors or xenografts of human tumor cells (Lammering et al, 2001a) and is rapidly lost in vitro (Bigner et al, 1990). In extension of previous studies on the role of EGFRvIII as an oncoprotein (Ekstrand et al, 1994;Nishikawa et al, 1994;Batra et al, 1995;Nagane et al, 1996;Huang et al, 1997), have started to define its involvement in cellular responses to genotoxic stress, such as ionizing radiation.…”