ErbB receptor tyrosine kinase network inhibition radiosensitizes carcinoma cells.
OBJECTIVE
The expression of epidermal growth factor receptor (EGFR)-CD533, a truncation mutant of the wild-type EGFR, radiosensitizes carcinoma and malignant glioma cell lines. This deletion mutant disrupts EGFR activation and downstream signaling through the formation of inhibitory dimerizations. In this study, the effects of EGFR-CD533 on other ErbB receptor tyrosine kinase (RTK) family members were quantified to better understand the mechanism of EGFR-CD533-mediated radiosensitization.


METHODS
Breast carcinoma cell lines with different ErbB RTK expression profiles were transduced with EGFR or ErbB2 deletion mutants (EGFR-CD533 and ErbB2-CD572) using an adenoviral vector. ErbB RTK activation, mitogen activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K)/p70S6K signaling, and clonogenic survival were determined for expression of each deletion mutant.


RESULTS
EGFR-CD533 radiosensitizes carcinoma cells with either high EGFR expression (MDA-MB231) or low EGFR expression (T47D) through significant blockade of the ErbB RTK network. Analysis of clonogenic survival demonstrate significant enhancement of the alpha/beta ratios, as determined by the linear-quadratic model. Split-dose survival experiments confirm that EGFR-CD533 reduces the repair of cellular damage after ionizing radiation.


CONCLUSIONS
Expression of EGFR-CD533 inhibits the ErbB RTK network and radiosensitizes carcinoma cells irrespective of the ErbB RTK expression patterns, and ErbB2-CD572 does not radiosensitize cells with low EGFR expression. These studies demonstrate that the mechanism of action for EGFR-CD533-mediated radiosensitization is inhibition of the ErbB RTK network, and is an advantage for radiosensitizing multiple malignant cell types.
Contessa
Joseph N
JN
Department of Radiation Oncology, Medical College of Virginia/Virginia Commonwealth University, Richmond VA, USA. jcontess@med.umich.edu
Abell
Angela
A
Valerie
Kristoffer
K
Lin
Peck-Sun
PS
Schmidt-Ullrich
Rupert K
RK
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3