Multiple responses to EGF receptor activation and their abrogation by a specific EGF receptor tyrosine kinase inhibitor.
BACKGROUND
Epidermal growth factor receptor (EGF-R) autophosphorylation is essential for its intracellular mitogenic signaling via the MAPK pathway and for interaction in other cellular processes. Inhibition of this activity in tumor cells that predominantly utilise EGF-R therefore offers an alternative approach to therapy.


METHODS
The ability of a specific inhibitor of EGF-R tyrosine kinase, ZM 252868, (TKI) to alter various parameters related to growth in DU145 and PC3 cell lines was investigated, by immunocytochemistry, Northern blotting, Western blotting and invasion assays.


RESULTS
In DU145 cultures, the total cell population and number of cells in cell cycle decreased in the presence of TKI whilst the apoptotic rate was significantly increased. Reduction in autophosphorylation of the EGF-R, membrane expression of EGF-R, activation of the MAPK, p38, and JNK enzymes and the invasive capacity of DU145 cells was observed in the TKI treated cells. Under the same conditions, PC3 cell growth and EGF-R expression and MAPK activation were not affected. The use of inhibitors of intracellular signaling indicated that the DU145 cells, in contrast to PC3 cells, predominantly utilize EGF-R activation of the MAPK signaling pathway for growth.


CONCLUSIONS
In prostatic cancer patients, in whom androgen resistance has developed and whose tumors have upregulated EGF-R for growth, specific TKI's may offer an important therapy option.
Harper
Maureen E
ME
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff, United Kingdom. HarperME1@Cardiff.ac.uk
Goddard
Lindy
L
Glynne-Jones
Eve
E
Assender
Jean
J
Dutkowski
Carol M
CM
Barrow
Denise
D
Dewhurst
Odette L
OL
Wakeling
Alan E
AE
Nicholson
Robert I
RI
D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; C106485:ZM 252868; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases